{"gene":"KIR3DL1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1994,"finding":"NKB1 (KIR3DL1) was identified as a ~70 kDa glycoprotein expressed on NK cell subsets that functions as an inhibitory receptor for certain HLA-B alleles (e.g., HLA-B*5101, B*5801); blocking with anti-NKB1 mAb DX9 reconstituted NK-cell lysis of HLA-B-expressing targets, demonstrating its role as an HLA-B recognition receptor.","method":"Anti-NKB1 mAb (DX9) blocking assays, NK cell clone cytotoxicity assays against HLA-B transfectants","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple NK clones, mAb blocking, HLA transfectants; foundational paper replicated subsequently","pmids":["8046332"],"is_preprint":false},{"year":1995,"finding":"The Bw4 epitope (residues 77–83) of HLA-B molecules is the determinant recognized by NKB1 (KIR3DL1)-expressing NK cells; HLA-B alleles bearing Bw4 inhibit NKB1+ NK killing, whereas Bw6-bearing alleles do not, and N-linked glycosylation at Asn86 is not essential for class I recognition by NKB1.","method":"NK cell cytotoxicity assays using HLA-B*1513 (Bw4) vs B*1502 (Bw6) transfectants; anti-NKB1 mAb reconstitution; site-directed mutagenesis of glycosylation site","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 — transfectants, mAb blocking, mutagenesis; replicated by multiple subsequent studies","pmids":["7532677"],"is_preprint":false},{"year":1995,"finding":"NKB1 (KIR3DL1) was cloned and determined to be an immunoglobulin superfamily member with three extracellular Ig-like domains (D0, D1, D2); after deglycosylation it migrates as ~50 kDa on SDS-PAGE, placing it in the KIR family of inhibitory receptors for HLA class I.","method":"cDNA cloning by expression in COS-7 cells using anti-NKB1 mAb DX9; SDS-PAGE with deglycosylation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — direct molecular cloning with expression validation; foundational structural characterization","pmids":["7650366"],"is_preprint":false},{"year":1995,"finding":"KIR3DL1 (NKB1) and the HLA-C receptor HP-3E4 are structurally distinct glycoproteins that independently recognize different polymorphic HLA molecules on the same NK clone; co-expression of both receptors requires antibodies against both to restore lysis, demonstrating independent signaling.","method":"Co-immunoprecipitation, flow cytometry, dual mAb blocking of NK cytotoxicity","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal blocking with two distinct mAbs on NK clones co-expressing both receptors","pmids":["7897214"],"is_preprint":false},{"year":1996,"finding":"The cytoplasmic ITIM (YxxL…YxxL) of KIR3DL1 (NKB1) mediates inhibitory signaling by recruiting protein tyrosine phosphatase PTP1C (SHP-1) upon tyrosine phosphorylation; mutation of both ITIM tyrosines abolished inhibitory function and PTP1C association, with the membrane-proximal tyrosine being especially critical.","method":"Jurkat T cell inhibition assay with NKB1 cytoplasmic domain constructs; co-immunoprecipitation of phosphorylated NKB1 with PTP1C; ITIM tyrosine point mutagenesis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro functional assay, Co-IP, mutagenesis of active-site residues; strong mechanistic evidence","pmids":["8691146"],"is_preprint":false},{"year":1997,"finding":"HLA-G inhibits NK lysis via NKAT3 (KIR3DL1); NK cell lines expressing NKAT3 are inhibited by HLA-G transfectants and by HLA-Bw4 molecules, and this inhibition is blocked by anti-NKAT3 antibody 5.133, extending KIR3DL1 ligand recognition to a non-classical HLA.","method":"NK cytotoxicity assay against HLA-G transfectants; anti-NKAT3 mAb blocking","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — functional inhibition assay with mAb blocking; single study","pmids":["9053439"],"is_preprint":false},{"year":1997,"finding":"Conserved Leu82 and Arg83 within the Bw4 motif contribute to but are not individually essential for NKB1 (KIR3DL1) recognition; polymorphisms distinguishing Bw4 motifs and residues outside the Bw4/Bw6 region (distinguishing HLA-B from HLA-A) also influence recognition.","method":"Site-directed mutagenesis of HLA-B Bw4/Bw6 residues; NK cell cytotoxicity and mAb blocking assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with functional NK assays; multiple Bw4 variants tested","pmids":["9164941"],"is_preprint":false},{"year":2001,"finding":"KIR3DL1 allelic polymorphism (not KIR3DL2) determines the level of DX9 antibody binding and NK cell surface expression; specific residues at positions 182 and 283 (extracellular domains), 320 (transmembrane), and 373 (cytoplasmic tail) distinguish high- vs. low/no-binding allotypes.","method":"KIR3DL1 allele sequencing in families and unrelated donors; flow cytometry of NK cell clones with DX9 and Z27 mAbs","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genotype-phenotype correlation in families and unrelated donors with clonal NK analysis; strong preponderance","pmids":["11207248"],"is_preprint":false},{"year":2003,"finding":"The KIR3DL1 promoter (~270 bp upstream of ATG) drives variegated expression and is active in multiple cell types, whereas KIR2DL4 promoter drives NK-restricted universal expression; the two promoters share 67% identity but have distinct transcription factor binding sites by DNase I footprinting.","method":"Reporter gene assays in multiple cell types; DNase I footprinting","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — promoter-reporter assays and footprinting; single study","pmids":["12794136"],"is_preprint":false},{"year":2005,"finding":"KIR3DL1 allotype *002 is a stronger inhibitory receptor for HLA-Bw4 ligands than *007; residue 238 in the D2 domain and residue 320 in the transmembrane region contribute to receptor strength without directly contacting HLA-Bw4; KIR3DL1 and LILRB1 both contribute to inhibitory response to HLA-Bw4.","method":"Retroviral transduction of human cell lines with defined alleles; NK inhibition assays; D2 and TM domain mutagenesis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis plus functional inhibition assays; defined allelic comparisons","pmids":["16210627"],"is_preprint":false},{"year":2005,"finding":"Crystal structures of HLA-B*2705 peptide complexes show that peptide residues at position 8 influence KIR3DL1 binding; complexes with charged amino acids at P8 (e.g., P8 Glu in EBV peptide) do not bind KIR3DL1, whereas substitution of P8 Glu to Thr allows KIR3DL1 recognition, demonstrating peptide-dependent KIR3DL1-HLA interaction.","method":"X-ray crystallography of HLA-B*2705-peptide complexes; KIR3DL1 tetramer binding assays; peptide mutagenesis","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus functional binding assay with mutagenesis","pmids":["15657948"],"is_preprint":false},{"year":2007,"finding":"KIR3DL1 inhibitory allotypes exhibit a consistent hierarchy of HLA-Bw4 ligand reactivity; the activating allele KIR3DS1, despite extracellular domain similarity, does not recognize HLA-Bw4 on EBV-transformed cell lines under tested conditions.","method":"NK cell killing assays with panel of KIR3DL1 allotypes; Z27 and DX9 flow cytometric staining of KIR3DS1+ NK cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — functional hierarchy defined across allotypes; replicated across donors","pmids":["17182560"],"is_preprint":false},{"year":2007,"finding":"HLA-B27 heterotrimers bind KIR3DL1 in a peptide-sequence-dependent manner (charged amino acids at P8 disrupt binding), whereas HLA-B27 homodimers (B27²) bind KIR3DL1 in a peptide-sequence-independent fashion; KIR3DL1 ligation by HLA-B27 inhibits NK cell IFN-γ production.","method":"KIR3DL1-transfected cell binding assays; HLA-B27 tetramer binding; IFN-γ functional assays with various peptide variants","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple peptide variants tested with transfectants and functional assays; two distinct HLA-B27 conformers compared","pmids":["17407096"],"is_preprint":false},{"year":2008,"finding":"HLA-A*2301, A*2402, and A*3201 (but not A*2501) are functional ligands for KIR3DL1, protecting target cells from lysis by KIR3DL1+ NK cells; HLA-A25 differs at position 90 near the Bw4 epitope, explaining its lack of recognition.","method":"NK cell cytotoxicity assays against HLA-A transfectants; flow cytometric analysis of KIR3DL1+ NK cell function","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — functional NK assays with defined HLA-A transfectants; extended KIR3DL1 ligand repertoire","pmids":["18502829"],"is_preprint":false},{"year":2008,"finding":"Polymorphisms outside the Bw4 epitope (positions 67 in α1, 116 in α2, and 194 in α3 domains) contribute to KIR3DL1 recognition of HLA-Bw4; these residues affect peptide binding pockets and influence the conformation of the Bw4 epitope, while position 83 (Arg) is essential for Bw4 functional activity.","method":"Systematic mutagenesis of HLA-B*5101 and B*1513 Bw4 epitope residues and distal positions; NK cell inhibition assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — comprehensive mutagenesis across all extracellular domains with functional NK readout","pmids":["18941220"],"is_preprint":false},{"year":2010,"finding":"KIR3DL1*004, a common allotype, is largely misfolded and retained in the endoplasmic reticulum (bound to chaperone calreticulin) without inducing the unfolded protein response; a small fraction folds correctly, reaches the cell surface, and can trigger NK cell inhibition upon interaction with HLA-Bw4.","method":"ER fractionation, co-immunoprecipitation with calreticulin, surface expression analysis by flow cytometry on primary NK and NKL cells, functional NK inhibition assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — fractionation, co-IP with chaperone, functional inhibition assay; mechanistic trafficking defined","pmids":["21115737"],"is_preprint":false},{"year":2011,"finding":"Common HIV-1 CTL escape mutations within the HLA-B57-restricted Gag epitope TSTLQEQIGW abrogate KIR3DL1 binding to HLA-B57, demonstrating that peptide variations modulate KIR3DL1-HLA-Bw4 interaction and NK cell sensing of viral escape.","method":"KIR3DL1 tetramer/recombinant protein binding assays to HLA-Bw4 complexed with variant peptides; NK cell functional assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — recombinant KIR3DL1 binding with defined peptide variants plus NK functional readout","pmids":["21471246"],"is_preprint":false},{"year":2014,"finding":"KIR3DL1 residue 282 (Glu) in the D2 domain is responsible for intolerance to negatively charged C-terminal peptide residues in peptide-HLA complexes; residue 283 (which differs between KIR3DL1 lineages) controls both peptide sensitivity and Bw4 subtype recognition; water-mediated contacts between KIR and HLA-presented peptide influence peptide binding specificity.","method":"Mutational analysis of KIR3DL1 residues combined with peptide-pHLA binding assays; NK cell functional assays with HIV Gag-derived epitopes","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis at specific residues with pHLA binding assays and functional NK readouts; defines molecular contacts","pmids":["24563253"],"is_preprint":false},{"year":2014,"finding":"KIR3DL1 Bw4 recognition requires the precise molecular architecture at HLA positions 80 (Ile) and 83 (Arg), which constrain the conformation of Glu76 via a salt bridge (Arg83–Glu76); this salt bridge is absent in Bw6 allotypes and in position-83 mutants, structurally explaining Bw4 vs Bw6 specificity.","method":"X-ray crystal structures of HLA-B*57:01, HLA-B*08:01, and Bw4/Bw6 position mutants; KIR3DL1+ NK and YTS cell inhibition assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — crystal structures combined with mutagenesis and functional assays; mechanistic basis of Bw4/Bw6 discrimination resolved","pmids":["25480565"],"is_preprint":false},{"year":2015,"finding":"KIR3DL1 binds the dengue NS1-derived HLA-B57-restricted peptide complex; NS1 tetramer binding to CD56dim NK cells was confirmed via KIR3DL1-transfected cell lines and depletion studies, showing KIR-HLA interactions modulate NK responses during acute dengue infection.","method":"Tetramer binding to NK cells; KIR-transfected cell lines; depletion studies","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct tetramer binding with transfectant confirmation; single study","pmids":["26439909"],"is_preprint":false},{"year":2015,"finding":"KIR3DS1-specific polymorphisms at positions 58 and 92 within the D0 extracellular domain of KIR3DL1*009 combinatorially disrupt surface expression and substantially reduce HLA-Bw4 binding; KIR3DL1*009+ NK cells exhibit less inhibition by HLA-Bw4+ targets than KIR3DL1*001+ NK cells.","method":"Flow cytometry of primary NK cells and transfected HEK293T cells; recombinant KIR3DL1 protein binding assays; site-directed mutagenesis of D0 domain positions 58 and 92","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis, recombinant protein binding, primary NK functional assays","pmids":["26109640"],"is_preprint":false},{"year":2015,"finding":"N-linked glycosylation of HLA class I (specifically HLA-B*57:01) is important for KIR3DL1 binding; inhibition of N-glycosylation with tunicamycin reduced KIR3DL1-Fc binding despite maintained HLA surface expression, leading to decreased KIR3DL1ζ+ Jurkat reporter activation and increased degranulation of primary KIR3DL1+ NK cells.","method":"Glycosylation enzyme inhibitors on HLA-B*57:01 cells; KIR3DL1-Fc binding assay; KIR3DL1ζ Jurkat reporter; primary NK cell degranulation assay","journal":"PLoS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods; single laboratory","pmids":["26680341"],"is_preprint":false},{"year":2016,"finding":"KIR3DL1 and HLA-B surface density calibrate NK cell education; high-density KIR3DL1/Bw4-80I partnerships confer the greatest NK reactivity; binding strength, receptor density, and ligand density are all functionally important parameters for education and cytotoxicity against HIV-infected cells.","method":"Flow cytometry of primary NK cells from genotyped donors; cytotoxicity assays against HLA-negative targets and HIV-infected autologous CD4+ T cells; KIR3DL1/HLA-B surface density quantification","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — primary human cells, multiple allele combinations, direct functional readouts; moderate-to-strong evidence","pmids":["26962229"],"is_preprint":false},{"year":2019,"finding":"CD8αα homodimers function as a coreceptor for KIR3DL1: CD8αα enhances pMHC-I binding to KIR3DL1, increases KIR3DL1 clustering at the immunological synapse, augments KIR3DL1-mediated inhibition of NK activation, and interactions between pMHC-I and CD8αα regulate KIR3DL1+ NK cell education.","method":"Co-immunoprecipitation, flow cytometry of immunological synapse, NK inhibition assays, education assays with CD8αα-expressing cells","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, synapse imaging, functional inhibition, education assays; multiple orthogonal methods","pmids":["31420518"],"is_preprint":false},{"year":2019,"finding":"The KIR3DL1 cytoplasmic region is intrinsically disordered with three functional segments; SHP-2 SH2 domains engage the unphosphorylated N-terminal ITIM (segment II), while bis-phosphorylated ITIMs drive more extensive conformational changes in segments I and III, implicating both ITIMs acting in concert to recruit the tandem SH2 domains of SHP-2.","method":"NMR spectroscopy of KIR3DL1 cytoplasmic domain constructs; SH2 domain binding assays with unphosphorylated and bis-phosphorylated ITIMs","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with functional binding validation; defines ITIM-SHP-2 engagement mechanism","pmids":["30773397"],"is_preprint":false},{"year":2019,"finding":"Mature peripheral KIR3DL1+ NK cells can be educated in vitro by co-culture with Bw4+HLA-B-expressing target cells; after training, KIR3DL1+ NK cells increase inflammatory and lytic responses to Bw4-negative targets, recapitulating in vivo education.","method":"In vitro co-culture education protocol; flow cytometric and cytotoxicity functional assays","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 — defined in vitro education system with functional readouts; single study","pmids":["31723004"],"is_preprint":false},{"year":2021,"finding":"ERAP1 controls the interaction of KIR3DL1 with HLA-B*51:01; genetic or pharmacological inhibition of ERAP1 in HLA-B*51:01-expressing cells impairs KIR3DL1 recognition, increasing NK cell degranulation specifically in the KIR3DL1-positive NK subset, identifying HLA-B*51:01/KIR3DL1 as especially sensitive to peptide repertoire changes.","method":"ERAP1 stable knockdown in 721.221 HLA transfectants; KIR3DL1-overexpressing YTS NK cell cytotoxicity assays; CD107a degranulation of primary KIR3DL1+ NK cells","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — KD plus functional assays; single study but orthogonal genetic and pharmacological approaches","pmids":["34917091"],"is_preprint":false}],"current_model":"KIR3DL1 is a polymorphic, three-Ig-domain inhibitory NK cell receptor that recognizes the Bw4 epitope (residues 77–83, critically Ile80 and Arg83, which stabilize Glu76 via a salt bridge) on HLA-B (and select HLA-A) allotypes in a peptide-sequence-sensitive manner; upon HLA-Bw4 ligation, its cytoplasmic ITIMs are tyrosine-phosphorylated and recruit SHP-2 (via its tandem SH2 domains engaging both ITIMs in concert) to suppress NK cell activation, with CD8αα homodimers acting as a coreceptor that enhances pMHC-I binding and KIR3DL1 clustering; allelic polymorphism throughout all extracellular domains and the transmembrane region modulates surface expression level and HLA-Bw4 binding affinity, calibrating NK cell education and effector strength."},"narrative":{"teleology":[{"year":1994,"claim":"Identifying the molecular identity of the NK inhibitory receptor for HLA-B established KIR3DL1 (NKB1) as a ~70 kDa glycoprotein whose blockade with mAb DX9 reconstituted NK killing of HLA-B+ targets, answering how NK cells discriminate HLA-B alleles.","evidence":"Anti-NKB1 mAb blocking of NK clone cytotoxicity against HLA-B transfectants","pmids":["8046332"],"confidence":"High","gaps":["Molecular structure unknown","Signaling mechanism undefined","Precise HLA-B epitope not mapped"]},{"year":1995,"claim":"Cloning revealed KIR3DL1 as a three-Ig-domain receptor, and functional assays mapped its specificity to the Bw4 serological epitope (residues 77–83) on HLA-B, establishing the structural framework and ligand specificity of the receptor.","evidence":"cDNA cloning with COS-7 expression; NK cytotoxicity assays with Bw4 vs Bw6 HLA-B transfectants and site-directed mutagenesis","pmids":["7650366","7532677"],"confidence":"High","gaps":["Residue-level contacts between KIR3DL1 and Bw4 unresolved","ITIM signaling pathway not yet defined"]},{"year":1996,"claim":"Demonstrating that ITIM tyrosine phosphorylation recruits the phosphatase SHP-1 (PTP1C) resolved the proximal signaling mechanism, with the membrane-proximal ITIM being especially critical for inhibitory function.","evidence":"Jurkat inhibition assay with cytoplasmic domain constructs; co-IP of phosphorylated NKB1 with PTP1C; ITIM tyrosine mutagenesis","pmids":["8691146"],"confidence":"High","gaps":["Role of SHP-2 vs SHP-1 not distinguished","Downstream phosphatase substrates unknown"]},{"year":1997,"claim":"Systematic Bw4 mutagenesis showed that Leu82 and Arg83 contribute to but are not individually essential for recognition, and residues outside the Bw4 motif also influence binding, revealing the complexity of the KIR3DL1–HLA interface.","evidence":"Site-directed mutagenesis of HLA-B Bw4/Bw6 residues with NK cytotoxicity assays","pmids":["9164941"],"confidence":"High","gaps":["Crystal structure of KIR3DL1–HLA complex not available","Peptide contribution to recognition unknown"]},{"year":2005,"claim":"Crystallographic and tetramer-binding studies established that the peptide presented by HLA-Bw4—particularly the P8 residue—directly modulates KIR3DL1 recognition, and allelic comparisons showed that D2 domain and transmembrane polymorphisms tune receptor strength without contacting HLA-Bw4.","evidence":"X-ray crystallography of HLA-B*2705–peptide complexes; KIR3DL1 tetramer binding with peptide mutagenesis; retroviral transduction of allelic variants with NK inhibition assays","pmids":["15657948","16210627"],"confidence":"High","gaps":["Full co-crystal of KIR3DL1 bound to HLA-Bw4 not yet solved","Mechanism by which TM residues affect function unclear"]},{"year":2008,"claim":"Extending the ligand repertoire to HLA-A allotypes (A*2301, A*2402, A*3201) and mapping contributions of distal positions (67, 116, 194) beyond the Bw4 epitope broadened understanding of KIR3DL1 ligand determinants and showed Arg83 is essential.","evidence":"NK cytotoxicity against HLA-A transfectants; systematic mutagenesis of HLA-B Bw4 and distal positions","pmids":["18502829","18941220"],"confidence":"High","gaps":["Structural basis for HLA-A vs HLA-B discrimination not resolved at atomic level"]},{"year":2010,"claim":"Discovery that KIR3DL1*004 is largely ER-retained due to misfolding (bound to calreticulin) explained why a common allotype has minimal surface expression yet retains low-level inhibitory function, linking protein quality control to NK receptor biology.","evidence":"ER fractionation, co-IP with calreticulin, flow cytometry, NK inhibition assay in NKL and primary NK cells","pmids":["21115737"],"confidence":"High","gaps":["Structural basis of *004 misfolding not defined","Whether ER-retained KIR3DL1 has signaling activity unknown"]},{"year":2014,"claim":"Crystal structures of HLA-Bw4 and Bw6 allotypes resolved the molecular basis of Bw4/Bw6 discrimination: Ile80 and Arg83 stabilize a Glu76 salt bridge present in Bw4 but absent in Bw6, while KIR3DL1 residues 282 and 283 in D2 govern peptide charge sensitivity via water-mediated contacts.","evidence":"X-ray crystal structures of HLA-B*57:01, HLA-B*08:01, and Bw4/Bw6 mutants; KIR3DL1 mutagenesis with pHLA binding and NK functional assays","pmids":["25480565","24563253"],"confidence":"High","gaps":["Full KIR3DL1–HLA-Bw4 co-crystal structure still lacking","Role of water-mediated contacts in vivo not confirmed"]},{"year":2016,"claim":"Quantitative analysis demonstrated that KIR3DL1 and HLA-B surface densities jointly calibrate NK cell education, with high-density KIR3DL1/Bw4-80I partnerships conferring the greatest reactivity, establishing a rheostat model for NK licensing.","evidence":"Flow cytometry with surface density quantification on genotyped primary NK cells; cytotoxicity against HLA-negative and HIV-infected targets","pmids":["26962229"],"confidence":"High","gaps":["Molecular mechanism coupling receptor density to education signaling threshold unknown"]},{"year":2019,"claim":"NMR structural studies of the intrinsically disordered KIR3DL1 cytoplasmic domain revealed that SHP-2 (not just SHP-1) engages both ITIMs in concert via its tandem SH2 domains, and identification of CD8αα as a coreceptor that enhances pMHC-I binding and KIR3DL1 clustering added a new layer to the inhibitory synapse architecture.","evidence":"NMR spectroscopy of cytoplasmic domain with SH2 binding assays; co-IP, synapse imaging, NK inhibition and education assays for CD8αα function","pmids":["30773397","31420518"],"confidence":"High","gaps":["Whether SHP-1 and SHP-2 act redundantly or sequentially in vivo unknown","Structural basis of CD8αα–KIR3DL1 cooperation not determined"]},{"year":2021,"claim":"ERAP1 trimming of the peptide repertoire was shown to be required for efficient KIR3DL1 recognition of HLA-B*51:01, linking antigen processing machinery to NK cell surveillance and identifying the KIR3DL1/HLA-B*51:01 axis as especially peptide-repertoire-sensitive.","evidence":"ERAP1 stable knockdown and pharmacological inhibition in HLA-B*51:01 transfectants; CD107a degranulation of primary KIR3DL1+ NK cells","pmids":["34917091"],"confidence":"Medium","gaps":["Specific peptides affected by ERAP1 loss not identified","Generalizability to other HLA-Bw4 alleles not tested","Single study without independent replication"]},{"year":null,"claim":"A high-resolution co-crystal structure of KIR3DL1 in complex with an HLA-Bw4 ligand and bound peptide has not been reported, leaving the full atomic details of the trimolecular interface unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No KIR3DL1–HLA-Bw4–peptide ternary co-crystal structure","Mechanism by which TM polymorphisms alter inhibitory strength unknown","How KIR3DL1 signaling integrates with CD8αα coreceptor clustering at the molecular level undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,24]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7,15,22]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,4,22,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,24]}],"complexes":[],"partners":["SHP-2","SHP-1","CD8A","CALR"],"other_free_text":[]},"mechanistic_narrative":"KIR3DL1 is a polymorphic, three-immunoglobulin-domain inhibitory receptor on NK cells that recognizes HLA class I molecules bearing the Bw4 epitope (residues 77–83), suppressing NK cell activation through ITIM-mediated recruitment of SHP-2 and calibrating NK cell education and effector function. Bw4 specificity is structurally determined by Ile80 and Arg83, which stabilize a salt bridge with Glu76 that is absent in Bw6 allotypes, and recognition is modulated by the sequence of HLA-bound peptide—particularly at the P8 position—and by ERAP1-dependent peptide trimming [PMID:25480565, PMID:15657948, PMID:34917091]. Upon HLA-Bw4 engagement, tyrosine-phosphorylated ITIMs in the intrinsically disordered cytoplasmic tail recruit the tandem SH2 domains of SHP-2, with both ITIMs acting in concert and the membrane-proximal ITIM being especially critical for inhibitory signaling [PMID:30773397, PMID:8691146]. Allelic polymorphism across all extracellular domains and the transmembrane region modulates surface expression level and HLA-Bw4 binding affinity, and CD8αα homodimers serve as a coreceptor that enhances pMHC-I binding, KIR3DL1 clustering, and NK cell inhibition [PMID:16210627, PMID:31420518]."},"prefetch_data":{"uniprot":{"accession":"P43629","full_name":"Killer cell immunoglobulin-like receptor 3DL1","aliases":["CD158 antigen-like family member E","HLA-BW4-specific inhibitory NK cell receptor","Natural killer-associated transcript 3","NKAT-3","p70 natural killer cell receptor clones CL-2/CL-11","p70 NK receptor CL-2/CL-11"],"length_aa":444,"mass_kda":49.1,"function":"Receptor on natural killer (NK) cells for HLA Bw4 allele. Inhibits the activity of NK cells thus preventing cell lysis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P43629/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIR3DL1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIR3DL1","total_profiled":1310},"omim":[{"mim_id":"620778","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, SHORT CYTOPLASMIC TAIL, 1; KIR3DS1","url":"https://www.omim.org/entry/620778"},{"mim_id":"610604","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, PSEUDOGENE 1; KIR3DP1","url":"https://www.omim.org/entry/610604"},{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"},{"mim_id":"605305","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, LONG CYTOPLASMIC TAIL, 5A; KIR2DL5A","url":"https://www.omim.org/entry/605305"},{"mim_id":"604955","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, SHORT CYTOPLASMIC TAIL, 4; KIR2DS4","url":"https://www.omim.org/entry/604955"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":1.4}],"url":"https://www.proteinatlas.org/search/KIR3DL1"},"hgnc":{"alias_symbol":["cl-2","NKB1","cl-11","nkat3","NKB1B","AMB11","CD158e1/2","CD158E1","CD158e2"],"prev_symbol":["KIR"]},"alphafold":{"accession":"P43629","domains":[{"cath_id":"2.60.40.10","chopping":"29-117","consensus_level":"high","plddt":78.0774,"start":29,"end":117},{"cath_id":"2.60.40.10","chopping":"122-216","consensus_level":"high","plddt":94.3437,"start":122,"end":216},{"cath_id":"2.60.40.10","chopping":"222-315","consensus_level":"high","plddt":93.6383,"start":222,"end":315}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43629","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43629-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43629-F1-predicted_aligned_error_v6.png","plddt_mean":75.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIR3DL1","jax_strain_url":"https://www.jax.org/strain/search?query=KIR3DL1"},"sequence":{"accession":"P43629","fasta_url":"https://rest.uniprot.org/uniprotkb/P43629.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43629/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43629"}},"corpus_meta":[{"pmid":"17496894","id":"PMC_17496894","title":"Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17496894","citation_count":613,"is_preprint":false},{"pmid":"7532677","id":"PMC_7532677","title":"The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor.","date":"1995","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7532677","citation_count":459,"is_preprint":false},{"pmid":"8046332","id":"PMC_8046332","title":"NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules.","date":"1994","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8046332","citation_count":354,"is_preprint":false},{"pmid":"7650366","id":"PMC_7650366","title":"Molecular cloning of NKB1. A natural killer cell receptor for HLA-B allotypes.","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7650366","citation_count":296,"is_preprint":false},{"pmid":"11207248","id":"PMC_11207248","title":"Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11207248","citation_count":214,"is_preprint":false},{"pmid":"17694054","id":"PMC_17694054","title":"Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17694054","citation_count":185,"is_preprint":false},{"pmid":"8691146","id":"PMC_8691146","title":"Phosphotyrosines in the killer cell inhibitory receptor motif of NKB1 are required for negative signaling and for association with protein tyrosine phosphatase 1C.","date":"1996","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8691146","citation_count":182,"is_preprint":false},{"pmid":"16210627","id":"PMC_16210627","title":"KIR3DL1 polymorphisms that affect NK cell inhibition by HLA-Bw4 ligand.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16210627","citation_count":175,"is_preprint":false},{"pmid":"20956340","id":"PMC_20956340","title":"Collectin 11 (CL-11, CL-K1) is a MASP-1/3-associated plasma collectin with microbial-binding activity.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20956340","citation_count":170,"is_preprint":false},{"pmid":"19386717","id":"PMC_19386717","title":"HLA class I subtype-dependent expansion of KIR3DS1+ and KIR3DL1+ NK cells during acute human immunodeficiency virus type 1 infection.","date":"2009","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/19386717","citation_count":156,"is_preprint":false},{"pmid":"9164941","id":"PMC_9164941","title":"Conserved and variable residues within the Bw4 motif of HLA-B make separable contributions to recognition by the NKB1 killer cell-inhibitory receptor.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9164941","citation_count":145,"is_preprint":false},{"pmid":"17182560","id":"PMC_17182560","title":"Functional polymorphism of the KIR3DL1/S1 receptor on human NK cells.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17182560","citation_count":141,"is_preprint":false},{"pmid":"8666938","id":"PMC_8666938","title":"Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype.","date":"1996","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8666938","citation_count":128,"is_preprint":false},{"pmid":"9053439","id":"PMC_9053439","title":"Human histocompatibility leukocyte antigen (HLA)-G molecules inhibit NKAT3 expressing natural killer cells.","date":"1997","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9053439","citation_count":118,"is_preprint":false},{"pmid":"28520526","id":"PMC_28520526","title":"KIR3DL1/HLA-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation.","date":"2017","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28520526","citation_count":118,"is_preprint":false},{"pmid":"26962229","id":"PMC_26962229","title":"KIR3DL1 and HLA-B Density and Binding Calibrate NK Education and Response to HIV.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26962229","citation_count":114,"is_preprint":false},{"pmid":"18502829","id":"PMC_18502829","title":"Human leukocyte antigens A23, A24, and A32 but not A25 are ligands for KIR3DL1.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18502829","citation_count":108,"is_preprint":false},{"pmid":"18614872","id":"PMC_18614872","title":"A combined genotype of KIR3DL1 high expressing alleles and HLA-B*57 is associated with a reduced risk of HIV infection.","date":"2008","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18614872","citation_count":108,"is_preprint":false},{"pmid":"17407096","id":"PMC_17407096","title":"Interaction of HLA-B27 homodimers with KIR3DL1 and KIR3DL2, unlike HLA-B27 heterotrimers, is independent of the sequence of bound peptide.","date":"2007","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17407096","citation_count":94,"is_preprint":false},{"pmid":"15657948","id":"PMC_15657948","title":"Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA-B*2705.","date":"2005","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15657948","citation_count":90,"is_preprint":false},{"pmid":"20061407","id":"PMC_20061407","title":"HIV protective KIR3DL1 and HLA-B genotypes influence NK cell function following stimulation with HLA-devoid cells.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20061407","citation_count":89,"is_preprint":false},{"pmid":"7897214","id":"PMC_7897214","title":"The NKB1 and HP-3E4 NK cells receptors are structurally distinct glycoproteins and independently recognize polymorphic HLA-B and HLA-C molecules.","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7897214","citation_count":84,"is_preprint":false},{"pmid":"21471235","id":"PMC_21471235","title":"Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21471235","citation_count":82,"is_preprint":false},{"pmid":"22475410","id":"PMC_22475410","title":"Structure and function of collectin liver 1 (CL-L1) and collectin 11 (CL-11, CL-K1).","date":"2012","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/22475410","citation_count":79,"is_preprint":false},{"pmid":"15784466","id":"PMC_15784466","title":"Interaction between KIR3DL1 and HLA-B*57 supertype alleles influences the progression of HIV-1 infection in a Zambian population.","date":"2005","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15784466","citation_count":70,"is_preprint":false},{"pmid":"27069083","id":"PMC_27069083","title":"KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma.","date":"2016","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27069083","citation_count":68,"is_preprint":false},{"pmid":"33207532","id":"PMC_33207532","title":"Bifunctional Bi12O17Cl2/MIL-100(Fe) composites toward photocatalytic Cr(VI) sequestration and activation of persulfate for bisphenol A degradation.","date":"2020","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/33207532","citation_count":61,"is_preprint":false},{"pmid":"16805919","id":"PMC_16805919","title":"Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations.","date":"2006","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/16805919","citation_count":60,"is_preprint":false},{"pmid":"21471246","id":"PMC_21471246","title":"Common HIV-1 peptide variants mediate differential binding of KIR3DL1 to HLA-Bw4 molecules.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21471246","citation_count":58,"is_preprint":false},{"pmid":"21690332","id":"PMC_21690332","title":"Variable NK cell receptors exemplified by human KIR3DL1/S1.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21690332","citation_count":57,"is_preprint":false},{"pmid":"24453969","id":"PMC_24453969","title":"HIV protective KIR3DL1/S1-HLA-B genotypes influence NK cell-mediated inhibition of HIV replication in autologous CD4 targets.","date":"2014","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24453969","citation_count":57,"is_preprint":false},{"pmid":"18941220","id":"PMC_18941220","title":"Polymorphic sites away from the Bw4 epitope that affect interaction of Bw4+ HLA-B with KIR3DL1.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18941220","citation_count":56,"is_preprint":false},{"pmid":"8437210","id":"PMC_8437210","title":"Fusion formation by the uncleaved spike protein of murine coronavirus JHMV variant cl-2.","date":"1993","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8437210","citation_count":53,"is_preprint":false},{"pmid":"23954398","id":"PMC_23954398","title":"Characterization of the interaction between collectin 11 (CL-11, CL-K1) and nucleic acids.","date":"2013","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23954398","citation_count":53,"is_preprint":false},{"pmid":"12381169","id":"PMC_12381169","title":"A new class of hybrid materials via salt inclusion: novel copper(II) arsenates Na(5)ACu(4)(AsO(4))(4)Cl(2) (A = Rb, Cs) composed of alternating covalent and ionic lattices.","date":"2002","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/12381169","citation_count":52,"is_preprint":false},{"pmid":"32073260","id":"PMC_32073260","title":"Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl2 Complexes.","date":"2020","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32073260","citation_count":46,"is_preprint":false},{"pmid":"20131260","id":"PMC_20131260","title":"Association of the KIR3DS1*013 and KIR3DL1*004 alleles with susceptibility to ankylosing spondylitis.","date":"2010","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/20131260","citation_count":46,"is_preprint":false},{"pmid":"24563253","id":"PMC_24563253","title":"Mutational and structural analysis of KIR3DL1 reveals a lineage-defining allotypic dimorphism that impacts both HLA and peptide sensitivity.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24563253","citation_count":45,"is_preprint":false},{"pmid":"32759055","id":"PMC_32759055","title":"[Pd(NHC)(μ-Cl)Cl]2: Versatile and Highly Reactive Complexes for Cross-Coupling Reactions that Avoid Formation of Inactive Pd(I) Off-Cycle Products.","date":"2020","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/32759055","citation_count":44,"is_preprint":false},{"pmid":"12794136","id":"PMC_12794136","title":"Different and divergent regulation of the KIR2DL4 and KIR3DL1 promoters.","date":"2003","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/12794136","citation_count":43,"is_preprint":false},{"pmid":"31932846","id":"PMC_31932846","title":"External validation of models for KIR2DS1/KIR3DL1-informed selection of hematopoietic cell donors fails.","date":"2020","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/31932846","citation_count":43,"is_preprint":false},{"pmid":"22345455","id":"PMC_22345455","title":"HIV infection abrogates the functional advantage of natural killer cells educated through KIR3DL1/HLA-Bw4 interactions to mediate anti-HIV antibody-dependent cellular cytotoxicity.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22345455","citation_count":42,"is_preprint":false},{"pmid":"26202228","id":"PMC_26202228","title":"A Higher Frequency of NKG2A+ than of NKG2A- NK Cells Responds to Autologous HIV-Infected CD4 Cells irrespective of Whether or Not They Coexpress KIR3DL1.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26202228","citation_count":39,"is_preprint":false},{"pmid":"24919192","id":"PMC_24919192","title":"Development of a novel multiplex PCR assay to detect functional subtypes of KIR3DL1 alleles.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24919192","citation_count":37,"is_preprint":false},{"pmid":"20818412","id":"PMC_20818412","title":"Contribution of functional KIR3DL1 to ankylosing spondylitis.","date":"2010","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20818412","citation_count":33,"is_preprint":false},{"pmid":"21398398","id":"PMC_21398398","title":"Under representation of the inhibitory KIR3DL1 molecule and the KIR3DL1+/BW4+ complex in HIV exposed seronegative individuals.","date":"2011","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21398398","citation_count":33,"is_preprint":false},{"pmid":"15219380","id":"PMC_15219380","title":"Investigation of killer cell immunoglobulin-like receptor gene diversity: IV. KIR3DL1/S1.","date":"2004","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15219380","citation_count":33,"is_preprint":false},{"pmid":"23756244","id":"PMC_23756244","title":"The yin-yang of KIR3DL1/S1: molecular mechanisms and cellular function.","date":"2013","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23756244","citation_count":32,"is_preprint":false},{"pmid":"34017328","id":"PMC_34017328","title":"Natural Killer Cells Generated From Human Induced Pluripotent Stem Cells Mature to CD56brightCD16+NKp80+/-In-Vitro and Express KIR2DL2/DL3 and KIR3DL1.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34017328","citation_count":32,"is_preprint":false},{"pmid":"21115737","id":"PMC_21115737","title":"Interactions of NK cell receptor KIR3DL1*004 with chaperones and conformation-specific antibody reveal a functional folded state as well as predominant intracellular retention.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21115737","citation_count":32,"is_preprint":false},{"pmid":"25480565","id":"PMC_25480565","title":"The interaction of KIR3DL1*001 with HLA class I molecules is dependent upon molecular microarchitecture within the Bw4 epitope.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25480565","citation_count":30,"is_preprint":false},{"pmid":"26439909","id":"PMC_26439909","title":"Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells.","date":"2015","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26439909","citation_count":29,"is_preprint":false},{"pmid":"23436464","id":"PMC_23436464","title":"Both the nature of KIR3DL1 alleles and the KIR3DL1/S1 allele combination affect the KIR3DL1 NK-cell repertoire in the French population.","date":"2013","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23436464","citation_count":29,"is_preprint":false},{"pmid":"26866467","id":"PMC_26866467","title":"The killer immunoglobulin-like receptor KIR3DL1 in combination with HLA-Bw4 is protective against multiple sclerosis in African Americans.","date":"2016","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/26866467","citation_count":27,"is_preprint":false},{"pmid":"22216211","id":"PMC_22216211","title":"Enrichment of variations in KIR3DL1/S1 and KIR2DL2/L3 among H1N1/09 ICU patients: an exploratory study.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22216211","citation_count":26,"is_preprint":false},{"pmid":"21797986","id":"PMC_21797986","title":"KIR3DL1+HLA-B Bw4Ile80 and KIR2DS1+HLA-C2 combinations are both associated with ankylosing spondylitis in the Iranian population.","date":"2011","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/21797986","citation_count":26,"is_preprint":false},{"pmid":"20364440","id":"PMC_20364440","title":"Metabolization of [Ru(eta(6)-C (6)H (5)CF (3))(pta)Cl (2)]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand.","date":"2010","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20364440","citation_count":25,"is_preprint":false},{"pmid":"20887224","id":"PMC_20887224","title":"Mind the gap: lack of association between KIR3DL1*004/HLA‐Bw4-induced natural killer cell function and protection from HIV infection.","date":"2010","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/20887224","citation_count":24,"is_preprint":false},{"pmid":"31858290","id":"PMC_31858290","title":"64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical study.","date":"2019","source":"EJNMMI research","url":"https://pubmed.ncbi.nlm.nih.gov/31858290","citation_count":23,"is_preprint":false},{"pmid":"30237800","id":"PMC_30237800","title":"Collectin-11 (CL-11) Is a Major Sentinel at Epithelial Surfaces and Key Pattern Recognition Molecule in Complement-Mediated Ischaemic Injury.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30237800","citation_count":22,"is_preprint":false},{"pmid":"21569835","id":"PMC_21569835","title":"Protective effects of fucoxanthin against ferric nitrilotriacetate-induced oxidative stress in murine hepatic BNL CL.2 cells.","date":"2011","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/21569835","citation_count":22,"is_preprint":false},{"pmid":"31420518","id":"PMC_31420518","title":"CD8αα homodimers function as a coreceptor for KIR3DL1.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31420518","citation_count":21,"is_preprint":false},{"pmid":"31849952","id":"PMC_31849952","title":"Association of Functional Polymorphisms of KIR3DL1/DS1 With Behçet's Disease.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31849952","citation_count":21,"is_preprint":false},{"pmid":"19859704","id":"PMC_19859704","title":"KIR3DL1/S1 genotypes and KIR2DS4 allelic variants in the AB KIR genotypes are associated with Plasmodium-positive individuals in malaria infection.","date":"2010","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19859704","citation_count":21,"is_preprint":false},{"pmid":"28412292","id":"PMC_28412292","title":"HLA-Bw4 80(T) and multiple HLA-Bw4 copies combined with KIR3DL1 associate with spontaneous clearance of HCV infection in people who inject drugs.","date":"2017","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/28412292","citation_count":21,"is_preprint":false},{"pmid":"28375571","id":"PMC_28375571","title":"HLA Mismatching Favoring Host-Versus-Graft NK Cell Activity Via KIR3DL1 Is Associated With Improved Outcomes Following Lung Transplantation.","date":"2017","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/28375571","citation_count":20,"is_preprint":false},{"pmid":"12779240","id":"PMC_12779240","title":"Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)] complex, a selective inhibitor of telomerase enzyme.","date":"2003","source":"Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12779240","citation_count":20,"is_preprint":false},{"pmid":"24173144","id":"PMC_24173144","title":"KIR3DL1 genetic diversity and phenotypic variation in the Chinese Han population.","date":"2013","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/24173144","citation_count":19,"is_preprint":false},{"pmid":"26990677","id":"PMC_26990677","title":"Hematopoietic stem cell transplantation: Improving alloreactive Bw4 donor selection by genotyping codon 86 of KIR3DL1/S1.","date":"2016","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26990677","citation_count":19,"is_preprint":false},{"pmid":"21924884","id":"PMC_21924884","title":"Inhibitory effect of plant-originated glycoprotein (27 kDa) on expression of matrix metalloproteinase-9 in cadmium chloride-induced BNL CL.2 cells.","date":"2011","source":"Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)","url":"https://pubmed.ncbi.nlm.nih.gov/21924884","citation_count":18,"is_preprint":false},{"pmid":"29421033","id":"PMC_29421033","title":"Biodegradation of fibrillated oil palm trunk fiber by a novel thermophilic, anaerobic, xylanolytic bacterium Caldicoprobacter sp. CL-2 isolated from compost.","date":"2017","source":"Enzyme and microbial technology","url":"https://pubmed.ncbi.nlm.nih.gov/29421033","citation_count":18,"is_preprint":false},{"pmid":"32370506","id":"PMC_32370506","title":"2D-3D Cs2PbI2Cl2-CsPbI2.5Br0.5 Mixed-Dimensional Films for All-Inorganic Perovskite Solar Cells with Enhanced Efficiency and Stability.","date":"2020","source":"The journal of physical chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/32370506","citation_count":18,"is_preprint":false},{"pmid":"20574122","id":"PMC_20574122","title":"Inhibitory Killer Cell Immunoglobulin-like Receptor KIR3DL1 in Combination with HLA-B Bw4iso Protect Against Ankylosing Spondylitis.","date":"2010","source":"Iranian journal of immunology : IJI","url":"https://pubmed.ncbi.nlm.nih.gov/20574122","citation_count":17,"is_preprint":false},{"pmid":"23420348","id":"PMC_23420348","title":"Regional differences in the expression of K(+)-Cl(-) 2 cotransporter in the developing rat cortex.","date":"2013","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/23420348","citation_count":17,"is_preprint":false},{"pmid":"24683193","id":"PMC_24683193","title":"Heterocomplex formation between MBL/ficolin/CL-11-associated serine protease-1 and -3 and MBL/ficolin/CL-11-associated protein-1.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24683193","citation_count":17,"is_preprint":false},{"pmid":"30290870","id":"PMC_30290870","title":"Effects of O3/Cl2 disinfection on corrosion and opportunistic pathogens growth in drinking water distribution systems.","date":"2018","source":"Journal of environmental sciences (China)","url":"https://pubmed.ncbi.nlm.nih.gov/30290870","citation_count":16,"is_preprint":false},{"pmid":"30323815","id":"PMC_30323815","title":"Development of a Quantitative Assay for the Characterization of Human Collectin-11 (CL-11, CL-K1).","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30323815","citation_count":16,"is_preprint":false},{"pmid":"28801811","id":"PMC_28801811","title":"Association of variably expressed KIR3dl1 alleles with psoriatic disease.","date":"2017","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/28801811","citation_count":15,"is_preprint":false},{"pmid":"21411516","id":"PMC_21411516","title":"Human immunodeficiency virus type 1 infection is associated with increased NK cell polyfunctionality and higher levels of KIR3DL1+ NK cells in ugandans carrying the HLA-B Bw4 motif.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21411516","citation_count":15,"is_preprint":false},{"pmid":"30528006","id":"PMC_30528006","title":"O3-BAC-Cl2: A multi-barrier process controlling the regrowth of opportunistic waterborne pathogens in drinking water distribution systems.","date":"2018","source":"Journal of environmental sciences (China)","url":"https://pubmed.ncbi.nlm.nih.gov/30528006","citation_count":15,"is_preprint":false},{"pmid":"10856432","id":"PMC_10856432","title":"Induction of apoptosis by the bis-Pt(III) complex [Pt(2)(2-mercaptopyrimidine)(4)Cl(2)].","date":"2000","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/10856432","citation_count":15,"is_preprint":false},{"pmid":"34673378","id":"PMC_34673378","title":"A [Pt(cis-1,3-diaminocycloalkane)Cl2] analog exhibits hallmarks typical of immunogenic cell death inducers in model cancer cells.","date":"2021","source":"Journal of inorganic biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34673378","citation_count":14,"is_preprint":false},{"pmid":"15916875","id":"PMC_15916875","title":"116 kDa glycoprotein isolated from Ulmus davidiana Nakai (UDN) inhibits glucose/glucose oxidase (G/GO)-induced apoptosis in BNL CL.2 cells.","date":"2005","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15916875","citation_count":14,"is_preprint":false},{"pmid":"26109640","id":"PMC_26109640","title":"KIR3DS1-Specific D0 Domain Polymorphisms Disrupt KIR3DL1 Surface Expression and HLA Binding.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26109640","citation_count":13,"is_preprint":false},{"pmid":"37409373","id":"PMC_37409373","title":"Cl2 ⋅- Mediates Direct and Selective Conversion of Inert C(sp3 )-H Bonds into Aldehydes/Ketones.","date":"2023","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/37409373","citation_count":12,"is_preprint":false},{"pmid":"15804184","id":"PMC_15804184","title":"Characterization of rPEPT2-mediated Gly-Sar transport parameters in the rat kidney proximal tubule cell line SKPT-0193 cl.2 cultured in basic growth media.","date":"2005","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/15804184","citation_count":12,"is_preprint":false},{"pmid":"30289808","id":"PMC_30289808","title":"Inhibitory natural killer cell receptor KIR3DL1 with its ligand Bw4 constraints HIV-1 disease among South Indians.","date":"2018","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/30289808","citation_count":11,"is_preprint":false},{"pmid":"34917091","id":"PMC_34917091","title":"ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34917091","citation_count":11,"is_preprint":false},{"pmid":"30147699","id":"PMC_30147699","title":"KIR3DL1-Negative CD8 T Cells and KIR3DL1-Negative Natural Killer Cells Contribute to the Advantageous Control of Early Human Immunodeficiency Virus Type 1 Infection in HLA-B Bw4 Homozygous Individuals.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30147699","citation_count":11,"is_preprint":false},{"pmid":"36511707","id":"PMC_36511707","title":"Bolaamphiphile Analogues of 12-bis-THA Cl2 Are Potent Antimicrobial Therapeutics with Distinct Mechanisms of Action against Bacterial, Mycobacterial, and Fungal Pathogens.","date":"2022","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/36511707","citation_count":11,"is_preprint":false},{"pmid":"26238044","id":"PMC_26238044","title":"Study on the protective effect of the KIR3DL1 gene in ankylosing spondylitis.","date":"2015","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/26238044","citation_count":11,"is_preprint":false},{"pmid":"38477971","id":"PMC_38477971","title":"Evaluating the Impact of Cl2•- Generation on Antibiotic-Resistance Contamination Removal via UV/Peroxydisulfate.","date":"2024","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/38477971","citation_count":11,"is_preprint":false},{"pmid":"20230527","id":"PMC_20230527","title":"The profile of KIR3DL1 and KIR3DS1 alleles in an African American population resembles that found in African populations.","date":"2010","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/20230527","citation_count":11,"is_preprint":false},{"pmid":"26321090","id":"PMC_26321090","title":"KIR3DL1 interaction with HLA-B27 is altered by ankylosing spondylitis associated ERAP1 and enhanced by MHC class I cross-linking.","date":"2015","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26321090","citation_count":10,"is_preprint":false},{"pmid":"9894849","id":"PMC_9894849","title":"Multiple transcripts of the killer cell immunoglobulin-like receptor family, KIR3DL1 (NKB1), are expressed by natural killer cells of a single individual.","date":"1998","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9894849","citation_count":10,"is_preprint":false},{"pmid":"38426876","id":"PMC_38426876","title":"On transient absorption and dual emission of the atomically precise, DNA-stabilized silver nanocluster Ag16Cl2.","date":"2024","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38426876","citation_count":10,"is_preprint":false},{"pmid":"8946681","id":"PMC_8946681","title":"Specificity of two anti-class I HLA monoclonal antibodies that block class I recognition by the NKB1 killer cell inhibitory receptor.","date":"1996","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/8946681","citation_count":9,"is_preprint":false},{"pmid":"30773397","id":"PMC_30773397","title":"Conformational Changes in the Cytoplasmic Region of KIR3DL1 upon Interaction with SHP-2.","date":"2019","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/30773397","citation_count":9,"is_preprint":false},{"pmid":"31723004","id":"PMC_31723004","title":"In vitro education of human natural killer cells by KIR3DL1.","date":"2019","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/31723004","citation_count":9,"is_preprint":false},{"pmid":"26680341","id":"PMC_26680341","title":"Influence of Glycosylation Inhibition on the Binding of KIR3DL1 to HLA-B*57:01.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26680341","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55494,"output_tokens":6708,"usd":0.133551},"stage2":{"model":"claude-opus-4-6","input_tokens":10416,"output_tokens":3112,"usd":0.19482},"total_usd":0.328371,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"NKB1 (KIR3DL1) was identified as a ~70 kDa glycoprotein expressed on NK cell subsets that functions as an inhibitory receptor for certain HLA-B alleles (e.g., HLA-B*5101, B*5801); blocking with anti-NKB1 mAb DX9 reconstituted NK-cell lysis of HLA-B-expressing targets, demonstrating its role as an HLA-B recognition receptor.\",\n      \"method\": \"Anti-NKB1 mAb (DX9) blocking assays, NK cell clone cytotoxicity assays against HLA-B transfectants\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple NK clones, mAb blocking, HLA transfectants; foundational paper replicated subsequently\",\n      \"pmids\": [\"8046332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The Bw4 epitope (residues 77–83) of HLA-B molecules is the determinant recognized by NKB1 (KIR3DL1)-expressing NK cells; HLA-B alleles bearing Bw4 inhibit NKB1+ NK killing, whereas Bw6-bearing alleles do not, and N-linked glycosylation at Asn86 is not essential for class I recognition by NKB1.\",\n      \"method\": \"NK cell cytotoxicity assays using HLA-B*1513 (Bw4) vs B*1502 (Bw6) transfectants; anti-NKB1 mAb reconstitution; site-directed mutagenesis of glycosylation site\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — transfectants, mAb blocking, mutagenesis; replicated by multiple subsequent studies\",\n      \"pmids\": [\"7532677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"NKB1 (KIR3DL1) was cloned and determined to be an immunoglobulin superfamily member with three extracellular Ig-like domains (D0, D1, D2); after deglycosylation it migrates as ~50 kDa on SDS-PAGE, placing it in the KIR family of inhibitory receptors for HLA class I.\",\n      \"method\": \"cDNA cloning by expression in COS-7 cells using anti-NKB1 mAb DX9; SDS-PAGE with deglycosylation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct molecular cloning with expression validation; foundational structural characterization\",\n      \"pmids\": [\"7650366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"KIR3DL1 (NKB1) and the HLA-C receptor HP-3E4 are structurally distinct glycoproteins that independently recognize different polymorphic HLA molecules on the same NK clone; co-expression of both receptors requires antibodies against both to restore lysis, demonstrating independent signaling.\",\n      \"method\": \"Co-immunoprecipitation, flow cytometry, dual mAb blocking of NK cytotoxicity\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal blocking with two distinct mAbs on NK clones co-expressing both receptors\",\n      \"pmids\": [\"7897214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The cytoplasmic ITIM (YxxL…YxxL) of KIR3DL1 (NKB1) mediates inhibitory signaling by recruiting protein tyrosine phosphatase PTP1C (SHP-1) upon tyrosine phosphorylation; mutation of both ITIM tyrosines abolished inhibitory function and PTP1C association, with the membrane-proximal tyrosine being especially critical.\",\n      \"method\": \"Jurkat T cell inhibition assay with NKB1 cytoplasmic domain constructs; co-immunoprecipitation of phosphorylated NKB1 with PTP1C; ITIM tyrosine point mutagenesis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro functional assay, Co-IP, mutagenesis of active-site residues; strong mechanistic evidence\",\n      \"pmids\": [\"8691146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HLA-G inhibits NK lysis via NKAT3 (KIR3DL1); NK cell lines expressing NKAT3 are inhibited by HLA-G transfectants and by HLA-Bw4 molecules, and this inhibition is blocked by anti-NKAT3 antibody 5.133, extending KIR3DL1 ligand recognition to a non-classical HLA.\",\n      \"method\": \"NK cytotoxicity assay against HLA-G transfectants; anti-NKAT3 mAb blocking\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional inhibition assay with mAb blocking; single study\",\n      \"pmids\": [\"9053439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Conserved Leu82 and Arg83 within the Bw4 motif contribute to but are not individually essential for NKB1 (KIR3DL1) recognition; polymorphisms distinguishing Bw4 motifs and residues outside the Bw4/Bw6 region (distinguishing HLA-B from HLA-A) also influence recognition.\",\n      \"method\": \"Site-directed mutagenesis of HLA-B Bw4/Bw6 residues; NK cell cytotoxicity and mAb blocking assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with functional NK assays; multiple Bw4 variants tested\",\n      \"pmids\": [\"9164941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"KIR3DL1 allelic polymorphism (not KIR3DL2) determines the level of DX9 antibody binding and NK cell surface expression; specific residues at positions 182 and 283 (extracellular domains), 320 (transmembrane), and 373 (cytoplasmic tail) distinguish high- vs. low/no-binding allotypes.\",\n      \"method\": \"KIR3DL1 allele sequencing in families and unrelated donors; flow cytometry of NK cell clones with DX9 and Z27 mAbs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genotype-phenotype correlation in families and unrelated donors with clonal NK analysis; strong preponderance\",\n      \"pmids\": [\"11207248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The KIR3DL1 promoter (~270 bp upstream of ATG) drives variegated expression and is active in multiple cell types, whereas KIR2DL4 promoter drives NK-restricted universal expression; the two promoters share 67% identity but have distinct transcription factor binding sites by DNase I footprinting.\",\n      \"method\": \"Reporter gene assays in multiple cell types; DNase I footprinting\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter-reporter assays and footprinting; single study\",\n      \"pmids\": [\"12794136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KIR3DL1 allotype *002 is a stronger inhibitory receptor for HLA-Bw4 ligands than *007; residue 238 in the D2 domain and residue 320 in the transmembrane region contribute to receptor strength without directly contacting HLA-Bw4; KIR3DL1 and LILRB1 both contribute to inhibitory response to HLA-Bw4.\",\n      \"method\": \"Retroviral transduction of human cell lines with defined alleles; NK inhibition assays; D2 and TM domain mutagenesis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis plus functional inhibition assays; defined allelic comparisons\",\n      \"pmids\": [\"16210627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structures of HLA-B*2705 peptide complexes show that peptide residues at position 8 influence KIR3DL1 binding; complexes with charged amino acids at P8 (e.g., P8 Glu in EBV peptide) do not bind KIR3DL1, whereas substitution of P8 Glu to Thr allows KIR3DL1 recognition, demonstrating peptide-dependent KIR3DL1-HLA interaction.\",\n      \"method\": \"X-ray crystallography of HLA-B*2705-peptide complexes; KIR3DL1 tetramer binding assays; peptide mutagenesis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus functional binding assay with mutagenesis\",\n      \"pmids\": [\"15657948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIR3DL1 inhibitory allotypes exhibit a consistent hierarchy of HLA-Bw4 ligand reactivity; the activating allele KIR3DS1, despite extracellular domain similarity, does not recognize HLA-Bw4 on EBV-transformed cell lines under tested conditions.\",\n      \"method\": \"NK cell killing assays with panel of KIR3DL1 allotypes; Z27 and DX9 flow cytometric staining of KIR3DS1+ NK cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional hierarchy defined across allotypes; replicated across donors\",\n      \"pmids\": [\"17182560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HLA-B27 heterotrimers bind KIR3DL1 in a peptide-sequence-dependent manner (charged amino acids at P8 disrupt binding), whereas HLA-B27 homodimers (B27²) bind KIR3DL1 in a peptide-sequence-independent fashion; KIR3DL1 ligation by HLA-B27 inhibits NK cell IFN-γ production.\",\n      \"method\": \"KIR3DL1-transfected cell binding assays; HLA-B27 tetramer binding; IFN-γ functional assays with various peptide variants\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple peptide variants tested with transfectants and functional assays; two distinct HLA-B27 conformers compared\",\n      \"pmids\": [\"17407096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HLA-A*2301, A*2402, and A*3201 (but not A*2501) are functional ligands for KIR3DL1, protecting target cells from lysis by KIR3DL1+ NK cells; HLA-A25 differs at position 90 near the Bw4 epitope, explaining its lack of recognition.\",\n      \"method\": \"NK cell cytotoxicity assays against HLA-A transfectants; flow cytometric analysis of KIR3DL1+ NK cell function\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional NK assays with defined HLA-A transfectants; extended KIR3DL1 ligand repertoire\",\n      \"pmids\": [\"18502829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Polymorphisms outside the Bw4 epitope (positions 67 in α1, 116 in α2, and 194 in α3 domains) contribute to KIR3DL1 recognition of HLA-Bw4; these residues affect peptide binding pockets and influence the conformation of the Bw4 epitope, while position 83 (Arg) is essential for Bw4 functional activity.\",\n      \"method\": \"Systematic mutagenesis of HLA-B*5101 and B*1513 Bw4 epitope residues and distal positions; NK cell inhibition assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — comprehensive mutagenesis across all extracellular domains with functional NK readout\",\n      \"pmids\": [\"18941220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KIR3DL1*004, a common allotype, is largely misfolded and retained in the endoplasmic reticulum (bound to chaperone calreticulin) without inducing the unfolded protein response; a small fraction folds correctly, reaches the cell surface, and can trigger NK cell inhibition upon interaction with HLA-Bw4.\",\n      \"method\": \"ER fractionation, co-immunoprecipitation with calreticulin, surface expression analysis by flow cytometry on primary NK and NKL cells, functional NK inhibition assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — fractionation, co-IP with chaperone, functional inhibition assay; mechanistic trafficking defined\",\n      \"pmids\": [\"21115737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Common HIV-1 CTL escape mutations within the HLA-B57-restricted Gag epitope TSTLQEQIGW abrogate KIR3DL1 binding to HLA-B57, demonstrating that peptide variations modulate KIR3DL1-HLA-Bw4 interaction and NK cell sensing of viral escape.\",\n      \"method\": \"KIR3DL1 tetramer/recombinant protein binding assays to HLA-Bw4 complexed with variant peptides; NK cell functional assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — recombinant KIR3DL1 binding with defined peptide variants plus NK functional readout\",\n      \"pmids\": [\"21471246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIR3DL1 residue 282 (Glu) in the D2 domain is responsible for intolerance to negatively charged C-terminal peptide residues in peptide-HLA complexes; residue 283 (which differs between KIR3DL1 lineages) controls both peptide sensitivity and Bw4 subtype recognition; water-mediated contacts between KIR and HLA-presented peptide influence peptide binding specificity.\",\n      \"method\": \"Mutational analysis of KIR3DL1 residues combined with peptide-pHLA binding assays; NK cell functional assays with HIV Gag-derived epitopes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis at specific residues with pHLA binding assays and functional NK readouts; defines molecular contacts\",\n      \"pmids\": [\"24563253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIR3DL1 Bw4 recognition requires the precise molecular architecture at HLA positions 80 (Ile) and 83 (Arg), which constrain the conformation of Glu76 via a salt bridge (Arg83–Glu76); this salt bridge is absent in Bw6 allotypes and in position-83 mutants, structurally explaining Bw4 vs Bw6 specificity.\",\n      \"method\": \"X-ray crystal structures of HLA-B*57:01, HLA-B*08:01, and Bw4/Bw6 position mutants; KIR3DL1+ NK and YTS cell inhibition assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures combined with mutagenesis and functional assays; mechanistic basis of Bw4/Bw6 discrimination resolved\",\n      \"pmids\": [\"25480565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIR3DL1 binds the dengue NS1-derived HLA-B57-restricted peptide complex; NS1 tetramer binding to CD56dim NK cells was confirmed via KIR3DL1-transfected cell lines and depletion studies, showing KIR-HLA interactions modulate NK responses during acute dengue infection.\",\n      \"method\": \"Tetramer binding to NK cells; KIR-transfected cell lines; depletion studies\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct tetramer binding with transfectant confirmation; single study\",\n      \"pmids\": [\"26439909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIR3DS1-specific polymorphisms at positions 58 and 92 within the D0 extracellular domain of KIR3DL1*009 combinatorially disrupt surface expression and substantially reduce HLA-Bw4 binding; KIR3DL1*009+ NK cells exhibit less inhibition by HLA-Bw4+ targets than KIR3DL1*001+ NK cells.\",\n      \"method\": \"Flow cytometry of primary NK cells and transfected HEK293T cells; recombinant KIR3DL1 protein binding assays; site-directed mutagenesis of D0 domain positions 58 and 92\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis, recombinant protein binding, primary NK functional assays\",\n      \"pmids\": [\"26109640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"N-linked glycosylation of HLA class I (specifically HLA-B*57:01) is important for KIR3DL1 binding; inhibition of N-glycosylation with tunicamycin reduced KIR3DL1-Fc binding despite maintained HLA surface expression, leading to decreased KIR3DL1ζ+ Jurkat reporter activation and increased degranulation of primary KIR3DL1+ NK cells.\",\n      \"method\": \"Glycosylation enzyme inhibitors on HLA-B*57:01 cells; KIR3DL1-Fc binding assay; KIR3DL1ζ Jurkat reporter; primary NK cell degranulation assay\",\n      \"journal\": \"PLoS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods; single laboratory\",\n      \"pmids\": [\"26680341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR3DL1 and HLA-B surface density calibrate NK cell education; high-density KIR3DL1/Bw4-80I partnerships confer the greatest NK reactivity; binding strength, receptor density, and ligand density are all functionally important parameters for education and cytotoxicity against HIV-infected cells.\",\n      \"method\": \"Flow cytometry of primary NK cells from genotyped donors; cytotoxicity assays against HLA-negative targets and HIV-infected autologous CD4+ T cells; KIR3DL1/HLA-B surface density quantification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — primary human cells, multiple allele combinations, direct functional readouts; moderate-to-strong evidence\",\n      \"pmids\": [\"26962229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD8αα homodimers function as a coreceptor for KIR3DL1: CD8αα enhances pMHC-I binding to KIR3DL1, increases KIR3DL1 clustering at the immunological synapse, augments KIR3DL1-mediated inhibition of NK activation, and interactions between pMHC-I and CD8αα regulate KIR3DL1+ NK cell education.\",\n      \"method\": \"Co-immunoprecipitation, flow cytometry of immunological synapse, NK inhibition assays, education assays with CD8αα-expressing cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, synapse imaging, functional inhibition, education assays; multiple orthogonal methods\",\n      \"pmids\": [\"31420518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The KIR3DL1 cytoplasmic region is intrinsically disordered with three functional segments; SHP-2 SH2 domains engage the unphosphorylated N-terminal ITIM (segment II), while bis-phosphorylated ITIMs drive more extensive conformational changes in segments I and III, implicating both ITIMs acting in concert to recruit the tandem SH2 domains of SHP-2.\",\n      \"method\": \"NMR spectroscopy of KIR3DL1 cytoplasmic domain constructs; SH2 domain binding assays with unphosphorylated and bis-phosphorylated ITIMs\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional binding validation; defines ITIM-SHP-2 engagement mechanism\",\n      \"pmids\": [\"30773397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mature peripheral KIR3DL1+ NK cells can be educated in vitro by co-culture with Bw4+HLA-B-expressing target cells; after training, KIR3DL1+ NK cells increase inflammatory and lytic responses to Bw4-negative targets, recapitulating in vivo education.\",\n      \"method\": \"In vitro co-culture education protocol; flow cytometric and cytotoxicity functional assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined in vitro education system with functional readouts; single study\",\n      \"pmids\": [\"31723004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERAP1 controls the interaction of KIR3DL1 with HLA-B*51:01; genetic or pharmacological inhibition of ERAP1 in HLA-B*51:01-expressing cells impairs KIR3DL1 recognition, increasing NK cell degranulation specifically in the KIR3DL1-positive NK subset, identifying HLA-B*51:01/KIR3DL1 as especially sensitive to peptide repertoire changes.\",\n      \"method\": \"ERAP1 stable knockdown in 721.221 HLA transfectants; KIR3DL1-overexpressing YTS NK cell cytotoxicity assays; CD107a degranulation of primary KIR3DL1+ NK cells\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD plus functional assays; single study but orthogonal genetic and pharmacological approaches\",\n      \"pmids\": [\"34917091\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIR3DL1 is a polymorphic, three-Ig-domain inhibitory NK cell receptor that recognizes the Bw4 epitope (residues 77–83, critically Ile80 and Arg83, which stabilize Glu76 via a salt bridge) on HLA-B (and select HLA-A) allotypes in a peptide-sequence-sensitive manner; upon HLA-Bw4 ligation, its cytoplasmic ITIMs are tyrosine-phosphorylated and recruit SHP-2 (via its tandem SH2 domains engaging both ITIMs in concert) to suppress NK cell activation, with CD8αα homodimers acting as a coreceptor that enhances pMHC-I binding and KIR3DL1 clustering; allelic polymorphism throughout all extracellular domains and the transmembrane region modulates surface expression level and HLA-Bw4 binding affinity, calibrating NK cell education and effector strength.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KIR3DL1 is a polymorphic, three-immunoglobulin-domain inhibitory receptor on NK cells that recognizes HLA class I molecules bearing the Bw4 epitope (residues 77–83), suppressing NK cell activation through ITIM-mediated recruitment of SHP-2 and calibrating NK cell education and effector function. Bw4 specificity is structurally determined by Ile80 and Arg83, which stabilize a salt bridge with Glu76 that is absent in Bw6 allotypes, and recognition is modulated by the sequence of HLA-bound peptide—particularly at the P8 position—and by ERAP1-dependent peptide trimming [PMID:25480565, PMID:15657948, PMID:34917091]. Upon HLA-Bw4 engagement, tyrosine-phosphorylated ITIMs in the intrinsically disordered cytoplasmic tail recruit the tandem SH2 domains of SHP-2, with both ITIMs acting in concert and the membrane-proximal ITIM being especially critical for inhibitory signaling [PMID:30773397, PMID:8691146]. Allelic polymorphism across all extracellular domains and the transmembrane region modulates surface expression level and HLA-Bw4 binding affinity, and CD8αα homodimers serve as a coreceptor that enhances pMHC-I binding, KIR3DL1 clustering, and NK cell inhibition [PMID:16210627, PMID:31420518].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identifying the molecular identity of the NK inhibitory receptor for HLA-B established KIR3DL1 (NKB1) as a ~70 kDa glycoprotein whose blockade with mAb DX9 reconstituted NK killing of HLA-B+ targets, answering how NK cells discriminate HLA-B alleles.\",\n      \"evidence\": \"Anti-NKB1 mAb blocking of NK clone cytotoxicity against HLA-B transfectants\",\n      \"pmids\": [\"8046332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular structure unknown\", \"Signaling mechanism undefined\", \"Precise HLA-B epitope not mapped\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Cloning revealed KIR3DL1 as a three-Ig-domain receptor, and functional assays mapped its specificity to the Bw4 serological epitope (residues 77–83) on HLA-B, establishing the structural framework and ligand specificity of the receptor.\",\n      \"evidence\": \"cDNA cloning with COS-7 expression; NK cytotoxicity assays with Bw4 vs Bw6 HLA-B transfectants and site-directed mutagenesis\",\n      \"pmids\": [\"7650366\", \"7532677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residue-level contacts between KIR3DL1 and Bw4 unresolved\", \"ITIM signaling pathway not yet defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that ITIM tyrosine phosphorylation recruits the phosphatase SHP-1 (PTP1C) resolved the proximal signaling mechanism, with the membrane-proximal ITIM being especially critical for inhibitory function.\",\n      \"evidence\": \"Jurkat inhibition assay with cytoplasmic domain constructs; co-IP of phosphorylated NKB1 with PTP1C; ITIM tyrosine mutagenesis\",\n      \"pmids\": [\"8691146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of SHP-2 vs SHP-1 not distinguished\", \"Downstream phosphatase substrates unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Systematic Bw4 mutagenesis showed that Leu82 and Arg83 contribute to but are not individually essential for recognition, and residues outside the Bw4 motif also influence binding, revealing the complexity of the KIR3DL1–HLA interface.\",\n      \"evidence\": \"Site-directed mutagenesis of HLA-B Bw4/Bw6 residues with NK cytotoxicity assays\",\n      \"pmids\": [\"9164941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of KIR3DL1–HLA complex not available\", \"Peptide contribution to recognition unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Crystallographic and tetramer-binding studies established that the peptide presented by HLA-Bw4—particularly the P8 residue—directly modulates KIR3DL1 recognition, and allelic comparisons showed that D2 domain and transmembrane polymorphisms tune receptor strength without contacting HLA-Bw4.\",\n      \"evidence\": \"X-ray crystallography of HLA-B*2705–peptide complexes; KIR3DL1 tetramer binding with peptide mutagenesis; retroviral transduction of allelic variants with NK inhibition assays\",\n      \"pmids\": [\"15657948\", \"16210627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full co-crystal of KIR3DL1 bound to HLA-Bw4 not yet solved\", \"Mechanism by which TM residues affect function unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extending the ligand repertoire to HLA-A allotypes (A*2301, A*2402, A*3201) and mapping contributions of distal positions (67, 116, 194) beyond the Bw4 epitope broadened understanding of KIR3DL1 ligand determinants and showed Arg83 is essential.\",\n      \"evidence\": \"NK cytotoxicity against HLA-A transfectants; systematic mutagenesis of HLA-B Bw4 and distal positions\",\n      \"pmids\": [\"18502829\", \"18941220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for HLA-A vs HLA-B discrimination not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that KIR3DL1*004 is largely ER-retained due to misfolding (bound to calreticulin) explained why a common allotype has minimal surface expression yet retains low-level inhibitory function, linking protein quality control to NK receptor biology.\",\n      \"evidence\": \"ER fractionation, co-IP with calreticulin, flow cytometry, NK inhibition assay in NKL and primary NK cells\",\n      \"pmids\": [\"21115737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of *004 misfolding not defined\", \"Whether ER-retained KIR3DL1 has signaling activity unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Crystal structures of HLA-Bw4 and Bw6 allotypes resolved the molecular basis of Bw4/Bw6 discrimination: Ile80 and Arg83 stabilize a Glu76 salt bridge present in Bw4 but absent in Bw6, while KIR3DL1 residues 282 and 283 in D2 govern peptide charge sensitivity via water-mediated contacts.\",\n      \"evidence\": \"X-ray crystal structures of HLA-B*57:01, HLA-B*08:01, and Bw4/Bw6 mutants; KIR3DL1 mutagenesis with pHLA binding and NK functional assays\",\n      \"pmids\": [\"25480565\", \"24563253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full KIR3DL1–HLA-Bw4 co-crystal structure still lacking\", \"Role of water-mediated contacts in vivo not confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Quantitative analysis demonstrated that KIR3DL1 and HLA-B surface densities jointly calibrate NK cell education, with high-density KIR3DL1/Bw4-80I partnerships conferring the greatest reactivity, establishing a rheostat model for NK licensing.\",\n      \"evidence\": \"Flow cytometry with surface density quantification on genotyped primary NK cells; cytotoxicity against HLA-negative and HIV-infected targets\",\n      \"pmids\": [\"26962229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism coupling receptor density to education signaling threshold unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"NMR structural studies of the intrinsically disordered KIR3DL1 cytoplasmic domain revealed that SHP-2 (not just SHP-1) engages both ITIMs in concert via its tandem SH2 domains, and identification of CD8αα as a coreceptor that enhances pMHC-I binding and KIR3DL1 clustering added a new layer to the inhibitory synapse architecture.\",\n      \"evidence\": \"NMR spectroscopy of cytoplasmic domain with SH2 binding assays; co-IP, synapse imaging, NK inhibition and education assays for CD8αα function\",\n      \"pmids\": [\"30773397\", \"31420518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SHP-1 and SHP-2 act redundantly or sequentially in vivo unknown\", \"Structural basis of CD8αα–KIR3DL1 cooperation not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ERAP1 trimming of the peptide repertoire was shown to be required for efficient KIR3DL1 recognition of HLA-B*51:01, linking antigen processing machinery to NK cell surveillance and identifying the KIR3DL1/HLA-B*51:01 axis as especially peptide-repertoire-sensitive.\",\n      \"evidence\": \"ERAP1 stable knockdown and pharmacological inhibition in HLA-B*51:01 transfectants; CD107a degranulation of primary KIR3DL1+ NK cells\",\n      \"pmids\": [\"34917091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific peptides affected by ERAP1 loss not identified\", \"Generalizability to other HLA-Bw4 alleles not tested\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution co-crystal structure of KIR3DL1 in complex with an HLA-Bw4 ligand and bound peptide has not been reported, leaving the full atomic details of the trimolecular interface unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No KIR3DL1–HLA-Bw4–peptide ternary co-crystal structure\", \"Mechanism by which TM polymorphisms alter inhibitory strength unknown\", \"How KIR3DL1 signaling integrates with CD8αα coreceptor clustering at the molecular level undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 24]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7, 15, 22]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 4, 22, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SHP-2\",\n      \"SHP-1\",\n      \"CD8A\",\n      \"CALR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}