Affinage

LY96

Lymphocyte antigen 96 · UniProt Q9Y6Y9

Length
160 aa
Mass
18.5 kDa
Annotated
2026-04-28
100 papers in source corpus 50 papers cited in narrative 50 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LY96 (MD-2) is an essential co-receptor of TLR4 that functions as the direct lipid-binding subunit of the innate immune endotoxin-sensing complex, governing LPS recognition, species-specific ligand discrimination, and downstream inflammatory signaling. MD-2 adopts a β-sandwich fold enclosing a deep hydrophobic pocket that accommodates acyl chains of LPS and diverse ligands (lipid IVa, taxol, sulfatides, heme, nickel ions); five of six LPS acyl chains are buried in this pocket while the sixth is exposed to contact a partner TLR4, driving assembly of the signaling-competent M-shaped 2:2:2 TLR4–MD-2–LPS heterohexamer that activates MyD88- and TRIF-dependent pathways (PMID:17569869, PMID:19252480, PMID:34290146). Monomeric MD-2 is the active TLR4-binding species (~12 nM Kd), receives endotoxin monomers sequentially from LBP and CD14, and is required for TLR4 surface trafficking; in its absence TLR4 is retained in the Golgi (PMID:12055629, PMID:16272300, PMID:15010525). MD-2 expression is regulated epigenetically by CpG methylation and transcriptionally by IFN-γ/JAK-STAT signaling; soluble MD-2 circulates as an acute-phase protein that opsonizes Gram-negative bacteria and enhances neutrophil phagocytosis (PMID:19710105, PMID:11923281, PMID:18056837).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1999 High

    The fundamental question of how TLR4 senses LPS was resolved by demonstrating that TLR4 alone is insufficient and requires a physically associated accessory protein, MD-2, for LPS responsiveness.

    Evidence Co-immunoprecipitation and functional LPS signaling assays in transfected cells

    PMID:10359581

    Open questions at the time
    • Mechanism of MD-2–TLR4 association unknown
    • Whether MD-2 directly contacts LPS or acts allosterically was unresolved
    • Stoichiometry of the signaling complex undefined
  2. 2001 High

    MD-2 was established as the direct LPS-binding subunit of the complex, binding LPS at ~65 nM Kd independently of LBP/CD14, while its monomeric form was identified as the preferential TLR4-binding species and species-specific ligand discrimination was mapped to MD-2 rather than TLR4.

    Evidence Recombinant MD-2 LPS-binding assays, SDS-PAGE oligomer analysis, site-directed mutagenesis, chimeric human/mouse MD-2–TLR4 NF-κB assays, and glycosylation mutagenesis

    PMID:11123270 PMID:11500507 PMID:11593030 PMID:11706042 PMID:11717200

    Open questions at the time
    • Three-dimensional structure of MD-2 unknown
    • Mechanism of LPS transfer from CD14 to MD-2 unresolved
    • Structural basis for species-specific discrimination unclear
  3. 2002 High

    MD-2 was shown to be required not only for signaling but also for TLR4 surface trafficking—without MD-2, TLR4 is retained in the Golgi—and to participate in recognition of minimally modified LDL, broadening its ligand scope beyond endotoxin.

    Evidence MD-2 knockout mouse with TLR4 subcellular localization analysis; CHO transfection with F-actin/mmLDL assays

    PMID:12055629 PMID:12424240

    Open questions at the time
    • Chaperone or escort mechanism for MD-2-dependent TLR4 trafficking uncharacterized
    • Whether MD-2 directly binds mmLDL lipids was not demonstrated
  4. 2003 High

    Systematic mutagenesis of all seven cysteines revealed that the Cys95–Cys105 intrachain disulfide is critical for LPS responsiveness, establishing the disulfide architecture that stabilizes the functional fold.

    Evidence Complete Cys-to-Ala mutagenesis with NF-κB reporter assays

    PMID:12642668

    Open questions at the time
    • No crystal structure yet to visualize disulfide geometry
    • Contribution of intermolecular disulfides to oligomer regulation not fully resolved
  5. 2004 High

    The sequential LPS transfer pathway LBP→CD14→MD-2→TLR4 was reconstituted, showing that a stable monomeric endotoxin·MD-2 complex activates TLR4 at picomolar concentrations, and MD-2 expression level was identified as the limiting factor for LPS responsiveness in airway epithelia.

    Evidence Purified endotoxin·MD-2 complex activation assays; adenoviral MD-2 rescue in human airway epithelial cells; mutagenesis of basic residue clusters

    PMID:15010525 PMID:15111623 PMID:15121639

    Open questions at the time
    • Structural mechanism of CD14-to-MD-2 lipid transfer unknown
    • Kinetics of sequential transfer not measured
  6. 2005 High

    Quantitative binding studies established MD-2's Kd for TLR4 (~12 nM), identified MD-2 as the molecular target for LPS antagonism by under-acylated lipids, mapped species-specificity determinant residues (Thr57, Val61, Glu122), and revealed that RP105/MD-1 inhibits TLR4 signaling by directly interacting with TLR4/MD-2.

    Evidence Competitive binding assays, serum sMD-2 depletion, chimeric MD-2 mutagenesis, co-immunoprecipitation of RP105

    PMID:16177092 PMID:16272300 PMID:16303092 PMID:16407172

    Open questions at the time
    • No atomic structure of full complex to rationalize antagonist/agonist switch
    • RP105/MD-1 interaction interface not mapped at residue level
  7. 2006 High

    Functional dissection separated LPS binding from receptor clustering (Phe126, Gly129), identified a hydrophobic pocket probe (bis-ANS) overlapping the LPS site, characterized IFN-γ/JAK-STAT-dependent transcriptional regulation, and showed trypsin proteolysis desensitizes intestinal MD-2.

    Evidence Alanine scanning mutagenesis, fluorescence binding, MD-2 promoter reporter assays with SOCS3 inhibition, biochemical proteolysis

    PMID:11923281 PMID:16547263 PMID:16670331 PMID:16940155

    Open questions at the time
    • No crystal structure yet for full-length complex
    • In vivo relevance of trypsin cleavage in intestinal tolerance not confirmed genetically
  8. 2007 High

    The crystal structure of human MD-2 alone and with lipid IVa (2.0–2.2 Å) revealed the deep hydrophobic β-sandwich cavity that fully encloses four acyl chains, providing the first atomic-level explanation for lipid binding and antagonist accommodation, and soluble MD-2 was identified as an acute-phase opsonin.

    Evidence X-ray crystallography; acute-phase induction in mice, hepatocyte secretion, opsonization-phagocytosis assay

    PMID:17569869 PMID:18056837

    Open questions at the time
    • Structure of agonist (hexa-acylated LPS) complex not yet solved
    • How the sixth acyl chain protrudes to contact TLR4 was not visible
  9. 2008 High

    Taxol was shown to bind directly to human MD-2 at the LPS-overlapping pocket, inducing conformational changes; species specificity of taxol TLR4 activation was mapped to murine MD-2 Phe126, and electrostatic surface potential changes in MD-2 and TLR4 enabling lipid IVa signaling were delineated.

    Evidence ELISA binding, competitive fluorescence displacement, CD spectroscopy, chimeric horse/human MD-2/TLR4 mutagenesis

    PMID:18606678 PMID:18650420 PMID:18977229

    Open questions at the time
    • No crystal structure of taxol-MD-2 complex
    • Structural basis of conformational change upon non-lipid ligand binding unresolved
  10. 2009 High

    The landmark crystal structure of the TLR4–MD-2–LPS heterohexamer revealed the M-shaped 2:2:2 signaling complex: five acyl chains buried in the MD-2 pocket, the sixth exposed chain contacting TLR4*, and ionic LPS phosphate interactions driving dimerization; Cys133 in the pocket was identified as a druggable thiol target, and epigenetic silencing of MD-2 by CpG methylation was demonstrated.

    Evidence X-ray crystallography of TLR4–MD-2–LPS; covalent Cys133 labeling with mass spectrometry and in vivo TNF-α assay; bisulfite sequencing with pharmacological reactivation

    PMID:19252480 PMID:19473973 PMID:19710105 PMID:20018893

    Open questions at the time
    • Dynamics of the sixth acyl chain exposure during activation not captured
    • Whether epigenetic silencing is reversible in vivo not tested
  11. 2010 High

    A splice variant (MD-2s) lacking exon 2 was characterized as a natural dominant-negative regulator that binds LPS and TLR4 but fails to signal, and additional species-specificity residues (Tyr42, Arg69, Asp122, Leu125) at the dimerization interface and TLR4 contact surface were mapped.

    Evidence Molecular cloning and co-immunoprecipitation of MD-2s; systematic mutagenesis of human/mouse MD-2

    PMID:20435923 PMID:20592019

    Open questions at the time
    • In vivo function of MD-2s isoform not tested in knockout models
    • Full structural model of MD-2s fold and its inability to promote dimerization lacking
  12. 2011 High

    Intracellular TLR4/MD-2 (in the absence of surface expression) was shown to sense phagocytosed bacteria and activate MyD88-dependent but not TRIF-dependent genes, establishing compartment-specific signaling, and albumin was identified as an alternative endotoxin carrier to MD-2.

    Evidence PRAT4A KO macrophages with cytokine profiling; purified endotoxin·albumin transfer assay with Kd measurement

    PMID:21712422 PMID:21994253

    Open questions at the time
    • Whether intracellular MD-2 source is recycled or newly synthesized is unknown
    • Physiological relevance of albumin-mediated transfer versus CD14-mediated transfer not quantified in vivo
  13. 2012 High

    Crystal structures of mouse TLR4/MD-2 with LPS and lipid IVa provided the structural explanation for species-specific agonism: lipid IVa adopts an agonistic orientation in mouse MD-2 (similar to LPS) but an entirely different antagonistic orientation in human MD-2.

    Evidence X-ray crystallography of mouse TLR4/MD-2/LPS and TLR4/MD-2/lipid IVa at 2.5–2.7 Å

    PMID:22532668

    Open questions at the time
    • How the pocket selects between orientations at the biophysical level remains unclear
    • No structure of human MD-2 with agonist hexa-acyl LPS for direct comparison
  14. 2013 High

    The ligand scope of MD-2 was further expanded to endogenous ligands (SAA3 binding at ~2.2 μM Kd, Gb4 competing with LPS), and the requirement for heterotetramer formation for full MyD88 signaling was quantified using monophosphoryl lipid A and MD-2 F126A.

    Evidence SPR for SAA3, co-precipitation and native PAGE for Gb4, A4galt KO mouse; MTS510 antibody heterotetramer assay

    PMID:23471986 PMID:23638128 PMID:23858030

    Open questions at the time
    • Structural basis for SAA3-MD-2 interaction unknown
    • Whether Gb4 inserts into the hydrophobic pocket or binds the surface not resolved
  15. 2015 High

    MD-2 was validated as a druggable target through small-molecule L6H21 binding to the hydrophobic pocket (Arg90, Tyr102), and the pocket was shown to mediate nickel/cobalt sensing through the same residues, revealing MD-2 as a sensor for transition metal allergens.

    Evidence SPR, molecular docking, MD-2 KO mouse sepsis model; site-directed mutagenesis for nickel/cobalt

    PMID:25803856 PMID:26076332

    Open questions at the time
    • Crystal structure of L6H21-MD-2 complex not obtained
    • Physiological relevance of nickel sensing through MD-2 in human contact allergy not directly demonstrated
  16. 2016 High

    The crystal structure of neoseptin-3 (a peptidomimetic) bound as an asymmetric dimer within the MD-2 pocket demonstrated that structurally unrelated non-lipid molecules can fully activate TLR4/MD-2, decoupling agonism from LPS-like structure.

    Evidence Crystal structure of mTLR4/MD-2/neoseptin-3 at 2.57 Å with NF-κB and MyD88/TRIF signaling assays

    PMID:26831104

    Open questions at the time
    • Whether neoseptin-3 induces identical downstream gene programs as LPS not determined
    • Human TLR4/MD-2 response to neoseptin-3 not tested
  17. 2017 High

    Soluble CD83 was identified as a new MD-2-binding immunomodulator that co-opts the TLR4/MD-2 axis to degrade IRAK-1 and induce tolerogenic mediators (IDO, IL-10, PGE2), establishing MD-2 as a receptor for immunosuppressive signaling.

    Evidence Binding partner identification, co-immunoprecipitation, IRAK-1 degradation, T cell proliferation assay

    PMID:28193829

    Open questions at the time
    • Binding affinity and stoichiometry of sCD83–MD-2 not quantified
    • Whether sCD83 occupies the hydrophobic pocket or binds externally is unknown
  18. 2018 High

    The two-stage binding model for HMGB1 was established: HMGB1 A-box binds TLR4 (high affinity, fast off-rate) while B-box binds MD-2 (low affinity, very slow off-rate), explaining how A-box peptide antagonizes HMGB1-driven inflammation.

    Evidence SPR kinetics with domain-specific recombinant proteins

    PMID:30134799

    Open questions at the time
    • Structural model of HMGB1-B-box/MD-2 interface lacking
    • Whether B-box occupies the lipid pocket not determined
  19. 2020 High

    A distinct heme-activation site on MD-2 (W23, Y34) was identified that is separate from the LPS-binding pocket, demonstrating that MD-2 harbors at least two functionally independent ligand-recognition surfaces.

    Evidence Heme-agarose pulldown of recombinant MD-2, UV/Vis spectroscopy, W23A/Y34A mutagenesis with NF-κB reporter

    PMID:32695117

    Open questions at the time
    • Structural basis of the heme site not determined crystallographically
    • Whether heme and LPS can simultaneously activate MD-2 not tested
  20. 2021 High

    Crystal structures of mouse TLR4-MD-2 with C16-sulfatide revealed three sulfatide molecules filling the pocket in an agonistic dimer geometry, extending the structural repertoire of pocket-bound endogenous lipids, and zebrafish ly96 was shown to be a functional MD-2 ortholog required for LPS-induced cytokine production.

    Evidence Crystal structure of mouse TLR4-MD-2/sulfatide; zebrafish loss-of-function mutant with NF-κB assay

    PMID:33472906 PMID:34290146

    Open questions at the time
    • Human TLR4/MD-2 sulfatide complex structure not available
    • Evolutionary conservation of the MD-2 pocket across vertebrates not systematically addressed
  21. 2023 High

    Disulfiram was shown to covalently modify Cys133 in the MD-2 pocket, blocking LPS sensing and TLR4 dimerization, and protecting dopaminergic neurons in a Parkinson's disease model, validating Cys133 as a therapeutic target for neuroinflammation.

    Evidence Covalent modification assay, Cys133 mutagenesis, TLR4 dimerization assay, MPTP mouse model

    PMID:37487070

    Open questions at the time
    • Selectivity of disulfiram for MD-2 Cys133 versus other cellular thiols not fully characterized
    • Long-term safety and efficacy in neurodegeneration models not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the dynamic mechanism by which CD14 transfers endotoxin monomers into the MD-2 pocket, the structural basis for heme recognition at the W23/Y34 site versus the canonical lipid pocket, and how intracellular versus surface TLR4/MD-2 complexes achieve compartment-specific signaling output.
  • No structure of CD14–MD-2 transfer intermediate
  • No crystal structure of heme-bound MD-2
  • Mechanism governing MyD88-only versus TRIF-dependent signaling from different compartments not fully resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 8 GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5
Partners
CD14CD83HMGB1LBPPTX3RP105SAA3TLR4
Complex memberships
RP105/MD-1/TLR4/MD-2TLR4/MD-2TLR4/MD-2/LPS heterohexamer

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 MD-2 (LY96) is physically associated with TLR4 on the cell surface and is required for LPS responsiveness; transfection of TLR4 alone does not confer LPS signaling, but co-expression with MD-2 does. Cell transfection, co-immunoprecipitation, functional LPS signaling assay The Journal of experimental medicine High 10359581
2001 MD-2 directly binds bacterial LPS with an apparent KD of ~65 nM, independent of LBP and CD14; LBP competes with MD-2 for LPS binding. Recombinant human MD-2 production, multiple LPS-binding assays including competitive binding The Journal of biological chemistry High 11500507
2001 MD-2 exists primarily as disulfide-linked oligomers; monomeric MD-2 preferentially binds TLR4 and confers LPS responsiveness more efficiently than multimeric forms. Intermolecular disulfide bonds (>2) stabilize the MD-2 multimer. Recombinant protein production, SDS-PAGE, site-directed mutagenesis, functional NF-κB reporter assay Proceedings of the National Academy of Sciences of the United States of America High 11593030
2001 Human MD-2 confers species-specific LPS recognition on TLR4: hMD-2 paired with mTLR4 confers responsiveness to lipid A but not lipid IVa, demonstrating that MD-2 directly determines the fine specificity of LPS recognition. Chimeric receptor transfection, NF-κB activation assay with lipid A and lipid IVa International immunology High 11717200
2001 N-linked glycosylation of MD-2 at Asn26 and Asn114 is required for full LPS-induced signaling (IL-8, JNK activation); the double glycosylation mutant fails to support LPS-induced NF-κB activation or IL-8 secretion, though cell surface expression of MD-2 is not dependent on these sites. Site-directed mutagenesis, cross-linking assay, luciferase reporter assay, JNK phosphorylation The Journal of biological chemistry High 11706042
2001 Gln22 of mouse MD-2 is essential for species-specific LPS-mimetic signaling by taxol but not for LPS signaling, demonstrating that MD-2 is responsible for taxol's species-specific activity. Site-directed mutagenesis of MD-2, NF-κB activation assay in transfected HEK293 cells Journal of immunology High 11123270
2002 MD-2 is essential for correct intracellular distribution and cell surface expression of TLR4; in MD-2−/− embryonic fibroblasts, TLR4 is retained in the Golgi apparatus rather than reaching the plasma membrane. MD-2 knockout mouse generation, subcellular fractionation/immunofluorescence of TLR4 localization, LPS challenge Nature immunology High 12055629
2002 MD-2 physically associates with both TLR4 and TLR2 (more weakly with TLR2), enables TLR2 to respond to LPS and lipid A, and enhances TLR2-mediated responses to Gram-negative bacteria and various bacterial ligands. Transfection of TLR2/TLR4 with MD-2, co-immunoprecipitation, chemokine production assay Journal of endotoxin research Medium 11521063
2002 Monomeric recombinant MD-2 binds TLR4 in solution; MD-2 multimerization is stabilized by more than two intermolecular disulfide bonds; monomeric form is the active TLR4-binding species. In vitro binding assay, SDS-PAGE, site-directed mutagenesis of Cys residues, NF-κB reporter assay The Journal of biological chemistry High 11976338
2003 The intrachain disulfide bond between Cys95 and Cys105 of MD-2 is critical for LPS responsiveness; substitution of either alone abolishes activity while substituting both partially restores it; most Cys residues lie on the surface and form inter/intrachain disulfide bridges. Site-directed mutagenesis of all 7 Cys residues, NF-κB reporter assay, structural analysis Proceedings of the National Academy of Sciences of the United States of America High 12642668
2004 MD-2 forms a stable monomeric bioactive complex with endotoxin monomer (generated via CD14), which at picomolar concentrations delivers endotoxin to TLR4 and activates cells; TLR4-dependent cell activation requires sequential transfer of endotoxin through LBP→CD14→MD-2→TLR4. Purification of endotoxin-MD-2 complex, cell activation assay at picomolar concentrations, competitive inhibition with excess MD-2 Proceedings of the National Academy of Sciences of the United States of America High 15010525
2004 Basic amino acid clusters Lys89-Arg90-Lys91 and Lys125-Lys125 on the surface of MD-2 are required for LPS signaling; these residues lie at the edge of the beta-sheet sandwich near the hydrophobic pocket. MD-2 adopts a beta-sandwich fold predicted by structural modeling and confirmed by CD spectroscopy. Structural homology modeling, CD spectroscopy, site-directed mutagenesis, functional LPS signaling assay The Journal of biological chemistry High 15111623
2005 Monomeric MD-2 (but not multimeric) binds TLR4 with apparent Kd of ~12 nM; LPS antagonist E5564 inhibits cellular activation by competitively preventing LPS binding to MD-2; endogenous soluble MD-2 in human serum (~50 nM) is required for TLR4-mediated LPS responses. Binding affinity measurement, competitive inhibition assay, depletion of soluble MD-2 from serum, TLR4-Fc fusion protein blocking Journal of immunology High 16272300
2005 MD-2 is the principal molecular target for LPS-dependent antagonism by under-acylated LPS (tetra-acylated P. gingivalis LPS and penta-acylated msbB LPS); antagonism occurs at soluble MD-2 and competitive binding to MD-2's LPS-binding site is the main mechanism. Immunoprecipitation of sCD14 and sMD-2, competitive binding, HEK293 reconstituted TLR4 system Journal of immunology High 16177092
2005 MD-2 amino acid regions 57–79 and 108–135, specifically residues Thr57, Val61, and Glu122, determine the agonist vs. antagonist activity of lipid IVa in a species-specific manner. Human/mouse chimeric MD-2 expression, site-directed mutagenesis, NF-κB activation assay The Journal of biological chemistry High 16407172
2006 MD-2 residue Gly59 is critical for LPS binding outside the 119–132 region; Phe126 and Gly129 of MD-2 regulate ligand-induced TLR4 receptor clustering independently of LPS binding; receptor clustering and dissociation depend on TLR4 signaling and endosomal acidification. MD-2 alanine scanning mutagenesis, LPS binding assay, TLR4 clustering assay by microscopy, endosomal acidification inhibition Journal of immunology High 16670331
2006 MD-2 has a hydrophobic binding pocket that is also recognized by the fluorescent probe bis-ANS with sub-10 nM affinity; the bis-ANS binding site overlaps with the LPS binding site near Trp of MD-2; photoincorporation of bis-ANS inhibits LPS responsiveness. Fluorescence binding assay, UV cross-linking/photoincorporation, NF-κB reporter assay FASEB journal High 16940155
2007 Crystal structure of human MD-2 alone and in complex with tetra-acylated lipid IVa at 2.0 and 2.2 Å: MD-2 has a deep hydrophobic cavity between two beta-sheets; four acyl chains of lipid IVa are fully enclosed in the cavity; phosphorylated glucosamine moieties sit at the cavity entrance. X-ray crystallography at 2.0 and 2.2 Å resolution Science High 17569869
2008 Paclitaxel binds human MD-2 in a dose-dependent and anti-MD-2 antibody-inhibitable manner; species specificity of paclitaxel TLR4 activation is determined by murine MD-2 (not TLR4); murine MD-2 Phe126 acts as a bridge for TLR4·MD-2 dimerization; paclitaxel binding pocket on MD-2 is characterized computationally. ELISA-based binding assay, chimeric receptor transfection, NF-κB activation assay, molecular docking The Journal of biological chemistry High 18650420
2008 Taxanes (paclitaxel and docetaxel) bind human MD-2 at a site overlapping with LPS and bis-ANS, inhibiting LPS signaling in human TLR4/MD-2 system; circular dichroism reveals conformational changes in human MD-2 upon taxane binding. Competitive fluorescence displacement, CD spectroscopy, molecular docking, NF-κB reporter assay FEBS letters High 18977229
2008 Discrete regions of MD-2 (residues 57–66 and 82–89) and TLR4 LRR14 in the C-terminus are required for lipid IVa-induced signaling; electrostatic surface potential changes in both MD-2 and TLR4 enable lipid IVa signaling; a single TLR4 residue in the glycan-free flank confers ability to respond to lipid IVa. Chimeric horse/human MD-2 and TLR4 expression, site-directed mutagenesis, NF-κB reporter assay Journal of immunology High 18606678
2009 Crystal structure of the TLR4-MD-2-LPS complex at atomic resolution reveals an M-shaped 2:2:2 heterohexamer; five of six LPS lipid chains are buried in MD-2's hydrophobic pocket; the sixth chain is exposed and contacts conserved TLR4 phenylalanines; LPS phosphate groups form ionic interactions with positively charged residues on TLR4 and MD-2 to drive dimerization; MD-2 F126 loop undergoes localized conformational change supporting the interface. X-ray crystallography of TLR4-MD-2-LPS complex Nature High 19252480
2009 Thiol-reactive compounds (fluorescent maleimides, auranofin, JTT-705) form covalent bonds with the free Cys133 of MD-2 and inhibit LPS-induced TLR4 signaling; Cys133 lies within the hydrophobic LPS-binding pocket and its modification blocks LPS signaling in vitro and in vivo. Covalent labeling, mass spectrometry identification of Cys133, NF-κB reporter assay, in vivo TNF-α production assay The Journal of biological chemistry High 19473973
2009 Both mouse TLR4 and mouse MD-2 are required for lipid IVa activation; ionic interactions between the 4'-phosphate of lipid IVa and positively charged mouse TLR4 residues Lys367 and Arg434 (absent in human) at the dimerization interface drive species-specific agonism; charge reversal mutations convert mouse to human-like responses and vice versa. Stable TLR4 cell lines, purified monomeric MD-2, MD-2-deficient macrophages, site-directed mutagenesis, computational modeling The Journal of biological chemistry High 20018893
2009 Morphine and other opioids non-stereoselectively bind to the LPS-binding pocket of MD-2 (in silico docking) and activate TLR4 signaling in vitro; this activity is blocked by classical TLR4 antagonists and by naloxone non-stereoselectively. In silico docking to MD-2 pocket, in vitro TLR4 signaling assay, TLR4 KO mouse, pharmacological blockade in vivo Brain, behavior, and immunity Medium 19679181
2010 MD-2 residues Tyr42, Arg69, Asp122, and Leu125 determine species-specific lipid IVa activation; residues 122 and 125 reside at the dimerization interface near the pocket entrance affecting receptor dimerization; residues 42 and 69 are at the MD-2/TLR4 interaction surface affecting binding angle. Systematic site-directed mutagenesis of human and mouse MD-2, NF-κB activation assay The Journal of biological chemistry High 20592019
2010 A novel alternatively spliced isoform of human MD-2, MD-2 short (MD-2s), lacking exon 2, is glycosylated and secreted, binds LPS and TLR4, but fails to activate NF-κB; MD-2s competitively inhibits MD-2 binding to TLR4 and negatively regulates LPS-induced TLR4 signaling; it is upregulated by IFN-γ, IL-6, and TLR4 stimulation. Molecular cloning, expression, co-immunoprecipitation, NF-κB reporter assay, competitive binding Journal of immunology High 20435923
2011 Intracellular TLR4/MD-2 in macrophages (those lacking PRAT4A-dependent cell surface expression) can sense phagocytosed bacteria and activate unique LPS-dependent gene sets (MyD88-dependent chemokines and co-stimulatory molecules) but not TRIF-dependent type I IFN production. PRAT4A KO macrophages, flow cytometry for surface TLR4, cytokine measurement, heat-killed bacteria stimulation International immunology High 21712422
2011 Endotoxin·albumin complexes transfer endotoxin monomers to MD-2 and MD-2·TLR4(ecd) with KD ~4 nM and activate TLR4-dependent cells independently of CD14, identifying albumin as an alternate endotoxin carrier to MD-2. Purified component binding assay, radiolabeled endotoxin transfer, cell activation assay Innate immunity High 21994253
2012 Crystal structures of mouse TLR4/MD-2/LPS and TLR4/MD-2/lipid IVa at 2.5 and 2.7 Å reveal that lipid IVa in mouse complex occupies nearly the same space as LPS and forms an agonistic 2:2:2 complex; human MD-2 binds lipid IVa in an entirely different antagonistic orientation. X-ray crystallography of mouse TLR4/MD-2/LPS and TLR4/MD-2/lipid IVa complexes Proceedings of the National Academy of Sciences of the United States of America High 22532668
2013 SAA3 (serum amyloid A3) directly binds MD-2 (not TLR4) with KD ~2.2 μM, activates p38 and NF-κB signaling via TLR4/MD-2/MyD88-dependent pathway, stimulates cell migration and IL-6/TNF-α production; this was demonstrated using synthetic peptides free of LPS contamination. Surface plasmon resonance, FLAG-tag co-precipitation, baculovirus coinfection, MyD88 KO cells, cytokine measurement Journal of immunology High 23858030
2013 Globotetraosylceramide (Gb4) binds directly to TLR4-MD-2 (demonstrated by co-precipitation with recombinant MD-2 and native PAGE) and competes with LPS, attenuating LPS toxicity; A4galt-deficient mice lacking Gb4 show higher LPS sensitivity. Co-precipitation with recombinant MD-2, native PAGE, A4galt KO mouse, docking model Proceedings of the National Academy of Sciences of the United States of America High 23471986
2014 PTX3 (long pentraxin 3) directly binds MD-2 in vitro and requires TLR4/MD-2-mediated TRIF-dependent signaling for antifungal immune protection; MD-2-deficient mice phenocopy TLR4-deficient mice in susceptibility to Aspergillus; PTX3-opsonized conidia activate TLR4/MD-2/TRIF/IL-10 pathway. In vitro binding assay, Md2 KO mouse, adoptive transfer, cytokine measurement Journal of immunology High 25049357
2015 Small molecule L6H21 inserts into the hydrophobic pocket of MD-2, forming hydrogen bonds with Arg90 and Tyr102, suppresses LPS-induced MAPK/NF-κB signaling in macrophages, and protects septic mice; MD-2 KO mice are protected from LPS shock, validating MD-2 as the therapeutic target. Molecular docking, SPR, ELISA, fluorescence assay, Western blot, MD-2 KO mouse, sepsis model British journal of pharmacology High 26076332
2016 Neoseptin-3 peptidomimetics bind as an asymmetric dimer within the MD-2 hydrophobic pocket (crystal structure at 2.57 Å), activate TLR4/MD-2 independently of CD14, and trigger canonical MyD88- and TRIF-dependent signaling, demonstrating that strong TLR4/MD-2 agonists need not mimic LPS structure. Chemical synthesis, crystal structure of mTLR4/MD-2/Neoseptin-3 at 2.57 Å, NF-κB reporter assay, MyD88/TRIF signaling assays Proceedings of the National Academy of Sciences of the United States of America High 26831104
2017 Soluble CD83 (sCD83) binds MD-2 as its high-affinity binding partner on monocytes, alters TLR4 signaling by rapidly degrading IRAK-1, and induces anti-inflammatory mediators (IDO, IL-10, PGE2 via COX-2), leading to T cell unresponsiveness. Binding partner identification, co-immunoprecipitation, IRAK-1 degradation Western blot, cytokine measurement, T cell proliferation assay Journal of immunology High 28193829
2018 HMGB1 interacts with TLR4/MD-2 in a two-stage process: the A-box domain binds TLR4 with high affinity (appreciable dissociation rate) while the B-box domain binds MD-2 with low affinity but very slow dissociation rate; A-box alone antagonizes HMGB1 by competitively blocking TLR4 interaction. Surface plasmon resonance (SPR) with recombinant proteins, domain-specific interaction mapping Molecular medicine High 30134799
2020 Heme binds MD-2 and activates TLR4 signaling requiring MD-2, TLR4, and CD14; MD-2 residues W23 and Y34 form a heme activation site (distinct from LPS site); W23A reduces heme-NF-κB activity 39% and Y34A by 78%; LPS activation is unaffected by these mutants. Heme-agarose/biotin-heme pulldown of recombinant MD-2, UV/visible spectroscopy, HEK293 transfection, NF-κB luciferase reporter, site-directed mutagenesis Frontiers in immunology High 32695117
2021 Crystal structure of mouse TLR4-MD-2 with C16-sulfatide at atomic resolution reveals three C16-sulfatide molecules bound to the MD-2 hydrophobic pocket, inducing an active 2:2 dimer conformation similar to LPS; short-chain sulfatides activate mouse TLR4-MD-2 (MyD88 and TRIF) while antagonizing human TLR4-MD-2, with activity dependent on the sulfate group and inversely related to fatty acid chain length. Crystal structure of mouse TLR4-MD-2/sulfatide, NF-κB reporter assay, TNF-α/IFN ELISA, MyD88/TRIF KO macrophages Proceedings of the National Academy of Sciences of the United States of America High 34290146
2021 Zebrafish LY96 (ly96) encodes an MD-2 ortholog expressed in macrophage-like innate immune cells; zebrafish Md-2 and Tlr4ba form a functional complex that activates NF-κB in response to LPS; ly96 loss-of-function perturbs LPS-induced cytokine production in larval zebrafish. Single-cell RNA-seq, functional NF-κB reporter assay in co-transfected cells, zebrafish loss-of-function mutants, cytokine measurement Journal of immunology High 33472906
2023 Disulfiram (DSF) inhibits TLR4 signaling by covalently modifying Cys133 of MD-2, blocking LPS sensing and dimerization; DSF suppresses neuroinflammation and dopaminergic neuron loss in a mouse model of Parkinson's disease in a TLR4-dependent manner. Covalent modification assay, mutagenesis of Cys133, TLR4 dimerization assay, macrophage cytokine assay, MPTP mouse model of Parkinson's disease Proceedings of the National Academy of Sciences of the United States of America High 37487070
2004 Low or absent expression of MD-2 in human airway epithelia explains their LPS unresponsiveness; adenoviral delivery of MD-2 or exogenous recombinant MD-2 increases LPS responsiveness >100-fold; bacterial products and TNF-α + IFN-γ can induce MD-2 mRNA in these cells. Adenoviral MD-2 transduction, recombinant MD-2 addition, NF-κB-luciferase assay, HBD-2 mRNA induction American journal of physiology. Lung cellular and molecular physiology High 15121639
2002 MD-2 and TLR4 are required for mmLDL-induced macrophage spreading (actin polymerization); CHO cells transfected with TLR4/MD-2 but not TLR4 alone or TLR2 show elevated F-actin response to mmLDL; CD14 is also involved in mmLDL binding. CHO cell transfection, J774 CD14-deficient mutant, C3H/HeJ macrophages, F-actin assay The Journal of biological chemistry High 12424240
2006 IFN-γ regulates MD-2 promoter activity through the JAK-STAT pathway; a STAT inhibitor (SOCS3) blocks IFN-γ-mediated MD-2 promoter activation; T-cell cytokines (IFN-γ, TNF-α) sensitize intestinal epithelial cells to LPS by upregulating MD-2. MD-2 promoter cloning, reporter assay, SOCS3 overexpression, cytokine treatment, RT-PCR, Western blot The Journal of biological chemistry High 11923281
2009 CpG methylation and histone deacetylation in the MD-2 promoter epigenetically silence MD-2 expression in intestinal epithelial cells; inhibition of methylation (5-azacytidine) or deacetylation (trichostatin A) restores MD-2 mRNA expression. Bisulfite sequencing of MD-2 promoter, 5-azacytidine and trichostatin A treatment, MD-2 mRNA measurement Innate immunity High 19710105
2007 Soluble MD-2 is a type II acute-phase protein: its mRNA and protein are upregulated in mouse liver after acute-phase induction, secreted by human hepatocytes, and upregulated by IL-6; sMD-2 opsonizes Gram-negative bacteria and accelerates/enhances phagocytosis by neutrophils. Acute-phase response induction in mice, hepatocyte secretion assay, IL-6 stimulation, opsonization-phagocytosis assay Blood High 18056837
2005 RP105/MD-1 directly interacts with TLR4/MD-2 and inhibits LPS binding to the TLR4/MD-2 signaling complex; RP105 is a specific physiological inhibitor of TLR4 signaling in dendritic cells and macrophages. Co-immunoprecipitation, LPS binding competition assay, HEK293 and primary cell functional assays Journal of endotoxin research High 16303092
2006 Trypsin proteolytically cleaves MD-2 at multiple trypsin cleavage sites in intestinal epithelial cells, causing desensitization to LPS; endogenous MD-2 is predominantly retained in the ER calnexin-calreticulin cycle in normal intestinal epithelium. Biochemical proteolysis assay, subcellular fractionation (ER localization), LPS responsiveness assay, IBD tissue analysis Journal of immunology High 16547263
2015 MD-2 residues Arg90 and Tyr102 mediate nickel/cobalt-induced TLR4 activation; nickel and cobalt activate human TLR4/MD-2 through TLR4 histidine residues (H456/H458 for cobalt) and require MD-2 for signal transduction, triggering both MyD88- and TRIF-dependent pathways. Site-directed mutagenesis of MD-2 and TLR4, NF-κB reporter assay, MyD88/TRIF pathway analysis PloS one High 25803856
2013 Monophosphoryl lipid A (sMLA/MPLA) does not efficiently drive TLR4/MD-2 heterotetramer formation compared to diphosphoryl lipid A, explaining its weak MyD88 signaling; MD-2 F126A mutant confirms that heterotetramer formation is required for full sMLA signaling activity. MTS510 antibody staining for heterotetramer detection, TRAF6 recruitment assay, MD-2 F126A mutagenesis, NF-κB/MAPK activation assays PloS one High 23638128

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 1865 19252480
1999 MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. The Journal of experimental medicine 1576 10359581
2002 Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nature immunology 792 12055629
2009 Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain, behavior, and immunity 431 19679181
2007 Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science (New York, N.Y.) 370 17569869
2002 Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. The Journal of biological chemistry 317 12424240
2002 TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. The Journal of biological chemistry 293 11923281
2000 Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. The Journal of biological chemistry 282 10644670
2004 Isolation of an endotoxin-MD-2 complex that produces Toll-like receptor 4-dependent cell activation at picomolar concentrations. Proceedings of the National Academy of Sciences of the United States of America 281 15010525
2012 Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2. Proceedings of the National Academy of Sciences of the United States of America 278 22532668
2004 Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2. Trends in microbiology 235 15051069
2001 MD-2 binds to bacterial lipopolysaccharide. The Journal of biological chemistry 230 11500507
2013 Recognition of lipid A variants by the TLR4-MD-2 receptor complex. Frontiers in cellular and infection microbiology 212 23408095
2001 MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor. The Journal of biological chemistry 203 11706042
2001 Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition. International immunology 196 11717200
2006 Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. Journal of immunology (Baltimore, Md. : 1950) 187 16785528
2001 Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4. Proceedings of the National Academy of Sciences of the United States of America 176 11593030
2005 MD-2 mediates the ability of tetra-acylated and penta-acylated lipopolysaccharides to antagonize Escherichia coli lipopolysaccharide at the TLR4 signaling complex. Journal of immunology (Baltimore, Md. : 1950) 147 16177092
2006 Regulatory roles for MD-2 and TLR4 in ligand-induced receptor clustering. Journal of immunology (Baltimore, Md. : 1950) 137 16670331
2004 Essential role of MD-2 in TLR4-dependent signaling during Helicobacter pylori-associated gastritis. Journal of immunology (Baltimore, Md. : 1950) 136 15240737
2016 TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS. Proceedings of the National Academy of Sciences of the United States of America 133 26831104
2004 Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2. American journal of physiology. Lung cellular and molecular physiology 128 15121639
2006 R-form LPS, the master key to the activation ofTLR4/MD-2-positive cells. European journal of immunology 126 16506285
2008 Unique properties of the chicken TLR4/MD-2 complex: selective lipopolysaccharide activation of the MyD88-dependent pathway. Journal of immunology (Baltimore, Md. : 1950) 124 18768894
2005 Pharmacological inhibition of endotoxin responses is achieved by targeting the TLR4 coreceptor, MD-2. Journal of immunology (Baltimore, Md. : 1950) 123 16272300
2008 Elucidation of the MD-2/TLR4 interface required for signaling by lipid IVa. Journal of immunology (Baltimore, Md. : 1950) 112 18606678
2014 Polymorphisms in the inflammatory pathway genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG are associated with susceptibility of inflammatory bowel disease in a Danish cohort. PloS one 104 24971461
2004 Structural model of MD-2 and functional role of its basic amino acid clusters involved in cellular lipopolysaccharide recognition. The Journal of biological chemistry 104 15111623
2007 TLR4/MD-2 monoclonal antibody therapy affords protection in experimental models of septic shock. Journal of immunology (Baltimore, Md. : 1950) 95 17947685
2003 Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2: unique roles for MD-2. International immunopharmacology 94 12538042
2004 Interaction of soluble form of recombinant extracellular TLR4 domain with MD-2 enables lipopolysaccharide binding and attenuates TLR4-mediated signaling. Journal of immunology (Baltimore, Md. : 1950) 90 15557191
2002 Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness. The Journal of biological chemistry 86 11976338
2009 MD-2-mediated ionic interactions between lipid A and TLR4 are essential for receptor activation. The Journal of biological chemistry 83 20018893
2015 MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsis. British journal of pharmacology 82 26076332
2020 Immunoinformatics approach to understand molecular interaction between multi-epitopic regions of SARS-CoV-2 spike-protein with TLR4/MD-2 complex. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 80 33039603
2018 Exploring the biological functional mechanism of the HMGB1/TLR4/MD-2 complex by surface plasmon resonance. Molecular medicine (Cambridge, Mass.) 80 30134799
2004 Endotoxin recognition molecules, Toll-like receptor 4-MD-2. Seminars in immunology 79 14751758
2014 Role of berberine in anti-bacterial as a high-affinity LPS antagonist binding to TLR4/MD-2 receptor. BMC complementary and alternative medicine 76 24602493
2008 Paclitaxel binding to human and murine MD-2. The Journal of biological chemistry 74 18650420
2000 Role of MD-2 in TLR2- and TLR4-mediated recognition of Gram-negative and Gram-positive bacteria and activation of chemokine genes. Journal of endotoxin research 74 11521063
2004 Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock. Blood 72 15328161
2005 Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria. International immunology 69 15908446
2015 Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment. Oncogene 66 26165843
2007 Kinetics of binding of LPS to recombinant CD14, TLR4, and MD-2 proteins. Molecules and cells 65 17846506
2013 Serum amyloid A3 binds MD-2 to activate p38 and NF-κB pathways in a MyD88-dependent manner. Journal of immunology (Baltimore, Md. : 1950) 64 23858030
2009 Regulation of Toll-like receptor 4-associated MD-2 in intestinal epithelial cells: a comprehensive analysis. Innate immunity 64 19710105
2015 Complete chloroplast genome sequence of MD-2 pineapple and its comparative analysis among nine other plants from the subclass Commelinidae. BMC plant biology 62 26264372
2012 Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica. PLoS pathogens 62 23071439
2003 The role of disulfide bonds in the assembly and function of MD-2. Proceedings of the National Academy of Sciences of the United States of America 60 12642668
2005 Structural regions of MD-2 that determine the agonist-antagonist activity of lipid IVa. The Journal of biological chemistry 59 16407172
2004 Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands by P. acnes involves up-regulation of MD-2 in mice. Hepatology (Baltimore, Md.) 59 15349893
2006 MD-2. Immunobiology 58 16920483
2023 Disulfiram blocks inflammatory TLR4 signaling by targeting MD-2. Proceedings of the National Academy of Sciences of the United States of America 56 37487070
2017 Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes. Journal of immunology (Baltimore, Md. : 1950) 56 28193829
2007 Antagonistic lipopolysaccharides block E. coli lipopolysaccharide function at human TLR4 via interaction with the human MD-2 lipopolysaccharide binding site. Cellular microbiology 56 17217428
2003 Overexpression of CD14, TLR4, and MD-2 in HEK 293T cells does not prevent induction of in vitro endotoxin tolerance. Journal of endotoxin research 56 12691621
2003 Role of TLR4/MD-2 and RP105/MD-1 in innate recognition of lipopolysaccharide. Scandinavian journal of infectious diseases 56 14620136
2002 Identification of LPS-binding peptide fragment of MD-2, a toll-receptor accessory protein. Biochemical and biophysical research communications 56 11944896
2001 Cutting edge: Gln22 of mouse MD-2 is essential for species-specific lipopolysaccharide mimetic action of taxol. Journal of immunology (Baltimore, Md. : 1950) 56 11123270
2008 Taxanes inhibit human TLR4 signaling by binding to MD-2. FEBS letters 55 18977229
2013 Conformationally constrained lipid A mimetics for exploration of structural basis of TLR4/MD-2 activation by lipopolysaccharide. ACS chemical biology 51 23952219
2019 LPS-induced CXCR7 expression promotes gastric Cancer proliferation and migration via the TLR4/MD-2 pathway. Diagnostic pathology 50 30636642
2021 Sulfatides are endogenous ligands for the TLR4-MD-2 complex. Proceedings of the National Academy of Sciences of the United States of America 49 34290146
2013 TLR4-MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide. Proceedings of the National Academy of Sciences of the United States of America 49 23471986
2005 Inhibition of TLR-4/MD-2 signaling by RP105/MD-1. Journal of endotoxin research 49 16303092
2014 PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis. Journal of immunology (Baltimore, Md. : 1950) 48 25049357
2010 Neisseria meningitidis capsular polysaccharides induce inflammatory responses via TLR2 and TLR4-MD-2. Journal of leukocyte biology 47 21191086
2014 The molecular mechanism of species-specific recognition of lipopolysaccharides by the MD-2/TLR4 receptor complex. Molecular immunology 46 25037631
2013 Modulation of CD14 and TLR4·MD-2 activities by a synthetic lipid A mimetic. Chembiochem : a European journal of chemical biology 46 24339336
2001 Involvement of TLR4/MD-2 complex in species-specific lipopolysaccharide-mimetic signal transduction by Taxol. Journal of endotoxin research 46 11581576
2005 Membrane-anchored CD14 is required for LPS-induced TLR4 endocytosis in TLR4/MD-2/CD14 overexpressing CHO cells. Biochemical and biophysical research communications 44 16263085
2004 Analysis of chicken TLR4, CD28, MIF, MD-2, and LITAF genes in a Salmonella enteritidis resource population. Poultry science 44 15109052
2006 Structural similarity between the hydrophobic fluorescent probe and lipid A as a ligand of MD-2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 16940155
2009 Free thiol group of MD-2 as the target for inhibition of the lipopolysaccharide-induced cell activation. The Journal of biological chemistry 41 19473973
2007 Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria. Blood 41 18056837
2015 Plasminogen activator inhibitor-1 regulates LPS-induced TLR4/MD-2 pathway activation and inflammation in alveolar macrophages. Inflammation 40 25342286
2011 Endotoxin{middle dot}albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4. Innate immunity 39 21994253
2016 Atractylenolide I modulates ovarian cancer cell-mediated immunosuppression by blocking MD-2/TLR4 complex-mediated MyD88/NF-κB signaling in vitro. Journal of translational medicine 38 27118139
2010 MD-2 residues tyrosine 42, arginine 69, aspartic acid 122, and leucine 125 provide species specificity for lipid IVA. The Journal of biological chemistry 38 20592019
2008 Lack of MD-2 expression in human corneal epithelial cells is an underlying mechanism of lipopolysaccharide (LPS) unresponsiveness. Immunology and cell biology 38 18936773
2006 Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance. Journal of immunology (Baltimore, Md. : 1950) 38 16547263
2011 Intracellular TLR4/MD-2 in macrophages senses Gram-negative bacteria and induces a unique set of LPS-dependent genes. International immunology 37 21712422
2011 From agonist to antagonist: structure and dynamics of innate immune glycoprotein MD-2 upon recognition of variably acylated bacterial endotoxins. Molecular immunology 36 21924775
2010 Expression of functional D299G.T399I polymorphic variant of TLR4 depends more on coexpression of MD-2 than does wild-type TLR4. Journal of immunology (Baltimore, Md. : 1950) 36 20212095
2008 Phagocytosis and intracellular killing of MD-2 opsonized gram-negative bacteria depend on TLR4 signaling. Blood 35 18203953
2002 Toll-like receptor 4-MD-2 complex mediates the signal transduction induced by flavolipin, an amino acid-containing lipid unique to Flavobacterium meningosepticum. Journal of immunology (Baltimore, Md. : 1950) 35 11884465
2007 MD-2 controls bacterial lipopolysaccharide hyporesponsiveness in human intestinal epithelial cells. Life sciences 34 18215718
2020 Identification of a Heme Activation Site on the MD-2/TLR4 Complex. Frontiers in immunology 33 32695117
2011 Electrochemical endotoxin sensors based on TLR4/MD-2 complexes immobilized on gold electrodes. Biosensors & bioelectronics 33 21816600
2010 Identification of a novel human MD-2 splice variant that negatively regulates Lipopolysaccharide-induced TLR4 signaling. Journal of immunology (Baltimore, Md. : 1950) 33 20435923
2021 Identification and Characterization of Zebrafish Tlr4 Coreceptor Md-2. Journal of immunology (Baltimore, Md. : 1950) 32 33472906
2012 The lipopolysaccharide from Capnocytophaga canimorsus reveals an unexpected role of the core-oligosaccharide in MD-2 binding. PLoS pathogens 32 22570611
2017 Loss of BMI-1 dampens migration and EMT of colorectal cancer in inflammatory microenvironment through TLR4/MD-2/MyD88-mediated NF-κB signaling. Journal of cellular biochemistry 31 28815730
2006 MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4). Journal of leukocyte biology 31 16946018
2015 MD-2 determinants of nickel and cobalt-mediated activation of human TLR4. PloS one 30 25803856
2007 Human MD-2 discrimination of meningococcal lipid A structures and activation of TLR4. Glycobiology 30 17545685
2005 MD-2 and Der p 2 - a tale of two cousins or distant relatives? Journal of endotoxin research 30 15949148
2011 Partially glycosylated dendrimers block MD-2 and prevent TLR4-MD-2-LPS complex mediated cytokine responses. PLoS computational biology 29 21738462
2013 Inefficient TLR4/MD-2 heterotetramerization by monophosphoryl lipid A. PloS one 28 23638128
2013 Anti-β2GPI/β2GPI stimulates activation of THP-1 cells through TLR4/MD-2/MyD88 and NF-κB signaling pathways. Thrombosis research 28 24157085