{"gene":"C2","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[],"current_model":"Parse failed"},"narrative":{"teleology":[],"mechanism_profile":null,"mechanistic_narrative":"Parse failed"},"prefetch_data":{"uniprot":{"accession":"P06681","full_name":"Complement C2","aliases":["C3/C5 convertase"],"length_aa":752,"mass_kda":83.3,"function":"Precursor of the catalytic component of the C3 and C5 convertase complexes, which are part of the complement pathway, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:12878586, PubMed:17027507, PubMed:18204047, PubMed:39914456, PubMed:39814882). Component C2 is part of the classical, lectin and GZMK complement systems (PubMed:12878586, PubMed:17027507, PubMed:18204047, PubMed:22691502, PubMed:39914456) Catalytic component of the complement C3 and C5 convertase complexes (PubMed:12878586, PubMed:17027507, PubMed:18204047, PubMed:6906228). Following complement activation, recruited to the surface of pathogens by complement C4b opsonin to form the C3 convertase, or C3b and C4b opsonins to form the C5 convertase (PubMed:6611150, PubMed:6906228). As part of the C3 convertase, cleaves and activate C3 into C3a anaphylatoxin and C3b opsonin, the next components of the complement pathways (PubMed:14561755, PubMed:17027507). As part of the C5 convertase, cleaves and activate C5 into C5a anaphylatoxin and C5b component of the membrane attack complex (PubMed:12878586, PubMed:17027507, PubMed:18204047)","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/P06681/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/C2","total_profiled":1310},"omim":[{"mim_id":"621518","title":"SYNAPTOTAGMIN 17; SYT17","url":"https://www.omim.org/entry/621518"},{"mim_id":"621499","title":"CRANIOSYNOSTOSIS-SCOLIOSIS SYNDROME; CRSS","url":"https://www.omim.org/entry/621499"},{"mim_id":"621370","title":"X KELL BLOOD GROUP PRECURSOR-RELATED FAMILY, MEMBER 9; XKR9","url":"https://www.omim.org/entry/621370"},{"mim_id":"621368","title":"X KELL BLOOD GROUP PRECURSOR-RELATED FAMILY, MEMBER 4; XKR4","url":"https://www.omim.org/entry/621368"},{"mim_id":"621206","title":"TRANSMEMBRANE AND IMMUNOGLOBULIN DOMAINS-CONTAINING PROTEIN 1; TMIGD1","url":"https://www.omim.org/entry/621206"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":454.7}],"url":"https://www.proteinatlas.org/search/C2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P06681","domains":[{"cath_id":"2.10.70.10","chopping":"33-85","consensus_level":"high","plddt":82.8091,"start":33,"end":85},{"cath_id":"2.10.70.10","chopping":"97-209","consensus_level":"high","plddt":91.3939,"start":97,"end":209},{"cath_id":"3.40.50.410","chopping":"244-453","consensus_level":"high","plddt":91.171,"start":244,"end":453},{"cath_id":"2.40.10.120","chopping":"473-705_713-743","consensus_level":"medium","plddt":94.0829,"start":473,"end":743}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06681","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06681-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06681-F1-predicted_aligned_error_v6.png","plddt_mean":88.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C2","jax_strain_url":"https://www.jax.org/strain/search?query=C2"},"sequence":{"accession":"P06681","fasta_url":"https://rest.uniprot.org/uniprotkb/P06681.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06681/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06681"}},"corpus_meta":[{"pmid":"8976547","id":"PMC_8976547","title":"The C2 domain calcium-binding motif: structural and functional diversity.","date":"1996","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/8976547","citation_count":709,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17719543","id":"PMC_17719543","title":"Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17719543","citation_count":231,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2858498","id":"PMC_2858498","title":"Rat medulla oblongata. 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ratios may be poor classifiers.","date":"2009","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19197355","citation_count":188,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19913121","id":"PMC_19913121","title":"Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19913121","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22691502","id":"PMC_22691502","title":"Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator of MASP-2.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22691502","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17576744","id":"PMC_17576744","title":"Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration.","date":"2007","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17576744","citation_count":153,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2949737","id":"PMC_2949737","title":"Primary structure of human complement component C2. Homology to two unrelated protein families.","date":"1986","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/2949737","citation_count":150,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16670774","id":"PMC_16670774","title":"Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2.","date":"2006","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/16670774","citation_count":146,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23533145","id":"PMC_23533145","title":"In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.","date":"2013","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23533145","citation_count":138,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19783065","id":"PMC_19783065","title":"Paths reunited: Initiation of the classical and lectin pathways of complement activation.","date":"2009","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/19783065","citation_count":122,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43276,"output_tokens":2574,"usd":0.084219},"stage2":{"model":"claude-opus-4-6","input_tokens":5770,"output_tokens":2244,"usd":0.127425},"total_usd":0.296739,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":56725,"output_tokens":1,"usd":0.085095},"round2_rules_fired":"R3"},"stage1_raw":"Looking at the corpus, I need to identify which \"C2\" gene is being queried. The corpus contains papers about complement component C2 (the second component of complement), which is a human gene encoding a serine protease involved in the classical and lectin complement pathways. I need to focus on mechanistic findings about this specific protein, excluding papers about C2 domains in other proteins, C2 myoblast cell lines, botulinum C2 toxin, phage c2 repressors, and other unrelated uses of \"C2.\"\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1984,\n      \"finding\": \"Complement C2 contains the catalytic site of the classical pathway C3 convertase (C4b2a). Amino acid sequence analysis of C2 and factor B revealed they are homologous novel serine proteinases; the catalytic chain C2a (509 residues) harbors the active site, while the non-catalytic chain C2b (223 residues) contains three tandem short consensus repeats homologous to those in complement regulatory proteins.\",\n      \"method\": \"Protein amino acid sequencing of CNBr peptides, structural homology analysis\",\n      \"journal\": \"Philosophical transactions of the Royal Society of London. Series B, Biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein sequencing and biochemical characterization, replicated across multiple labs\",\n      \"pmids\": [\"6149575\", \"6149579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"The human C2 gene is encoded within the class III region of the major histocompatibility complex (MHC), closely linked (<500 bp) to factor B. DNA-mediated gene transfer of cosmid DNA encoding human C2 into mouse L cells resulted in secretion of biologically active human C2 protein, confirming single-gene encoding of a functional serine protease complement component.\",\n      \"method\": \"DNA-mediated gene transfer into L cells, Northern blot, functional hemolytic assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gene transfer with functional readout (hemolytic activity), replicated with molecular and protein-level evidence\",\n      \"pmids\": [\"3850903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"The factor B gene (closely linked to C2) spans ~6 kb and contains 18 exons. The C2 gene spans ~18 kb with a similar 18-exon structure. Southern blot analysis confirmed single loci for both genes separated by less than 1 kb.\",\n      \"method\": \"Cosmid library screening, Southern blot, DNA sequencing\",\n      \"journal\": \"Philosophical transactions of the Royal Society of London. Series B, Biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct DNA sequencing and Southern blot, replicated across studies\",\n      \"pmids\": [\"6149579\", \"3902623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Full-length human C2 cDNA was cloned from a liver library and expressed in COS cells, producing secreted recombinant C2 with antigenicity and hemolytic activity identical to native serum C2. The mature polypeptide encodes 732 amino acids preceded by a 20-amino-acid signal peptide. The cDNA revealed a 5' untranslated region with upstream ATG codons followed by in-frame stop codons.\",\n      \"method\": \"cDNA cloning, COS cell transfection and expression, Western blot, hemolytic activity assay, Northern blot\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of functional protein from cloned cDNA with multiple orthogonal validation methods\",\n      \"pmids\": [\"2493504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human C2 gene structure was fully characterized: 18 exons spanning 18 kb of DNA. The three short consensus repeats (SCRs) of C2b are each encoded by single exons (exons 2, 3, 4); the von Willebrand factor type A-like domain of C2a is encoded by exons 6–10; and the serine protease domain by exons 11–18. Exon 5 appears unique to C2 and factor B genes.\",\n      \"method\": \"Nucleotide sequencing of exon-containing subclones, Southern blotting of cosmid clone S22A\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete gene structure determination by direct sequencing with functional domain mapping\",\n      \"pmids\": [\"8326124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"C2 and factor B share 39% sequence homology (50% with conservative substitutions). The catalytic chains C2a and Bb show homology to other serine proteases in their C-terminal domains, while the non-catalytic chains C2b and Ba each contain three tandem ~60 amino acid repeats homologous to C4b-binding protein and factor H repeats, establishing C2 as a novel chimeric serine protease with complement-regulatory repeat modules.\",\n      \"method\": \"Protein sequence analysis, structural comparison with known serine proteases and complement proteins\",\n      \"journal\": \"Biochemical Society symposium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein sequencing with structural/functional domain identification, consistent with multiple independent studies\",\n      \"pmids\": [\"3101701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The Schistosoma parasite protein Sh-TOR (subsequently named CRIT — complement C2 receptor inhibitor trispanning) binds human complement C2 specifically through its N-terminal extracellular domain (Sh-TOR-ed1), and pre-incubation with C2 inhibits classical pathway-mediated haemolysis. The interaction is with the C2a fragment and the inhibitory mechanism involves competition with C4b for C2 binding, preventing C3 convertase formation.\",\n      \"method\": \"Co-incubation binding assay, classical pathway haemolysis inhibition assay, sequence comparison with C4b\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional inhibition assay with mechanistic interpretation, single lab\",\n      \"pmids\": [\"10734221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The most common form of hereditary C2 deficiency in Caucasians is caused by a 28 base pair deletion in the C2 gene (in exon 6), identifiable by PCR and gel electrophoresis, and is significantly associated with the HLA DRB1*1501 allele, indicating this mutation arose on a specific MHC haplotype.\",\n      \"method\": \"PCR amplification with gel electrophoresis to distinguish wild-type vs. mutant alleles, population genetics\",\n      \"journal\": \"The Journal of rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular characterization of disease-causing mutation with defined genetic mechanism\",\n      \"pmids\": [\"7932427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARGX-117, a humanized monoclonal antibody targeting the Sushi-2 (short consensus repeat 2) domain of C2, prevents formation of the C3 proconvertase, thereby inhibiting both classical and lectin pathway activation upstream of C3 without affecting the alternative pathway. In cynomolgus monkeys, it dose-dependently reduced free C2 levels and classical pathway activity.\",\n      \"method\": \"In vitro complement cytotoxicity assays, surface plasmon resonance for binding characterization, in vivo pharmacokinetic/pharmacodynamic study in cynomolgus monkeys\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic mode-of-action established in vitro and in vivo with domain-level precision, multiple orthogonal methods\",\n      \"pmids\": [\"32926878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"Activation of complement C2 occurs through a novel mechanism compared to classical serine proteinases: C2 is cleaved by C1s when bound to C4b, generating C2a (the catalytic serine protease chain containing the active site) and C2b (the non-catalytic fragment with SCR repeats). The C3 convertase is then formed by C4b retaining C2a on its surface.\",\n      \"method\": \"Protein biochemistry, amino acid sequence determination, functional enzyme activity assays\",\n      \"journal\": \"Philosophical transactions of the Royal Society of London. Series B, Biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — protein sequencing combined with functional convertase assays, foundational biochemical characterization replicated across labs\",\n      \"pmids\": [\"6149575\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Complement component C2 is a serine protease encoded by a single gene in the MHC class III region; upon cleavage by C1s when bound to C4b, it generates C2a (the catalytic chain containing the serine protease active site) that remains surface-associated with C4b to form the classical/lectin pathway C3 convertase (C4b2a), while C2b (carrying three short consensus repeats homologous to complement regulatory proteins) is released; therapeutic antibodies targeting C2's Sushi-2 domain can block C3 proconvertase formation and inhibit both classical and lectin pathways without affecting the alternative pathway.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Complement component C2 is a serine protease zymogen of the classical and lectin complement pathways that, upon cleavage by C1s while bound to C4b, generates the catalytic fragment C2a and the released fragment C2b, with C2a remaining associated with C4b to form the C3 convertase (C4b2a) [PMID:6149575, PMID:2493504]. The mature 732-amino-acid protein is a chimeric molecule: the C-terminal C2a chain contains a von Willebrand factor type A–like domain and a serine protease domain, while the N-terminal C2b chain harbors three short consensus repeats (SCRs/Sushi domains) homologous to complement regulatory proteins such as C4b-binding protein and factor H [PMID:6149575, PMID:3101701, PMID:8326124]. The C2 gene resides in the MHC class III region within ~500 bp of its paralog factor B, spans 18 kb with 18 exons, and encodes a protein with 39% sequence identity to factor B [PMID:3850903, PMID:3902623, PMID:8326124]. Homozygous hereditary C2 deficiency, most commonly caused by a 28-bp deletion in exon 6 linked to the HLA-DRB1*1501 haplotype, is the most frequent complement deficiency in Caucasians and predisposes to immune complex–mediated disease [PMID:7932427].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Determination that C2 is a novel serine protease and that its catalytic fragment C2a forms the enzymatic subunit of the classical pathway C3 convertase answered the fundamental question of how C3 cleavage is achieved in the classical pathway.\",\n      \"evidence\": \"Amino acid sequencing of CNBr peptides of C2 and factor B combined with functional convertase assays\",\n      \"pmids\": [\"6149575\", \"6149579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal structure of C2 or the C4b2a convertase complex\",\n        \"Mechanism by which C4b binding enables C1s-mediated cleavage of C2 not defined\",\n        \"Precise catalytic residues inferred by homology, not directly proven\"\n      ]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Mapping C2 to the MHC class III region and demonstrating that a single gene produces functional hemolytically active C2 upon transfer into heterologous cells established the genomic context and sufficiency of the locus.\",\n      \"evidence\": \"DNA-mediated gene transfer of cosmid DNA into mouse L cells, hemolytic assay, Southern blot showing <500 bp separation from factor B\",\n      \"pmids\": [\"3850903\", \"3902623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Regulatory elements controlling C2 tissue-specific expression not characterized\",\n        \"Functional consequences of tight C2–factor B linkage unexplained\"\n      ]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"Quantification of 39% sequence identity between C2 and factor B, and identification of C2 as a chimeric protein combining SCR modules with a serine protease domain, defined the domain architecture underlying dual substrate-recognition and catalytic functions.\",\n      \"evidence\": \"Protein sequence comparison with known serine proteases and complement regulatory proteins\",\n      \"pmids\": [\"3101701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for differential substrate specificity between C2a and Bb not resolved\",\n        \"Role of individual SCR domains in C4b binding not dissected\"\n      ]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Cloning of full-length C2 cDNA and expression of functional recombinant protein confirmed the complete primary structure (732 residues plus signal peptide) and enabled downstream mutagenesis studies.\",\n      \"evidence\": \"cDNA cloning from human liver library, COS cell expression, hemolytic activity assay, Western blot\",\n      \"pmids\": [\"2493504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Post-translational modifications not characterized\",\n        \"Significance of upstream ATGs in 5′ UTR for translational regulation unknown\"\n      ]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Complete exon–intron mapping of C2 (18 exons over 18 kb) showed that each SCR, the vWF-A domain, and the serine protease domain are encoded by discrete exon blocks, revealing modular evolutionary assembly.\",\n      \"evidence\": \"Nucleotide sequencing of cosmid subclones, Southern blotting\",\n      \"pmids\": [\"8326124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional role of the unique exon 5 shared only with factor B not determined\",\n        \"Intron-based regulatory elements not explored\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of the 28-bp deletion in exon 6 as the molecular basis of type I hereditary C2 deficiency, on a specific MHC haplotype, connected gene structure to the most common human complement deficiency.\",\n      \"evidence\": \"PCR-based genotyping, HLA association analysis in C2-deficient individuals\",\n      \"pmids\": [\"7932427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Effect of the deletion on mRNA stability versus protein truncation not fully dissected\",\n        \"Genotype–phenotype correlation for disease severity not established\",\n        \"Type II C2 deficiency molecular basis not addressed\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery that the parasite-derived protein CRIT competes with C4b for C2a binding to block C3 convertase formation revealed an immune evasion mechanism and localized a key C4b-interaction site on the C2a fragment.\",\n      \"evidence\": \"Co-incubation binding assays and classical pathway hemolysis inhibition using recombinant CRIT extracellular domain\",\n      \"pmids\": [\"10734221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding interface on C2a not mapped at residue resolution\",\n        \"In vivo relevance of CRIT-C2 interaction not demonstrated in animal infection model\",\n        \"Independent confirmation by a second laboratory not reported\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Development of ARGX-117, targeting the Sushi-2 domain of C2, demonstrated that blocking C3 proconvertase formation at the level of C2 selectively inhibits classical and lectin pathways while sparing the alternative pathway, providing domain-level functional resolution.\",\n      \"evidence\": \"Surface plasmon resonance binding, in vitro complement cytotoxicity assays, in vivo pharmacokinetics/pharmacodynamics in cynomolgus monkeys\",\n      \"pmids\": [\"32926878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-level structural basis of Sushi-2–C4b interaction not resolved\",\n        \"Long-term immunological consequences of selective C2 inhibition in humans unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of the C4b2a convertase complex and the conformational changes accompanying C2 activation remain unresolved, limiting mechanistic understanding of substrate specificity, allosteric regulation, and rational inhibitor design.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of C4b2a holoenzyme\",\n        \"Allosteric regulation of C2a catalytic activity upon C4b binding not characterized\",\n        \"Role of individual SCR domains in pathway-specific recognition not dissected by mutagenesis\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 9, 3]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8, 9, 6]}\n    ],\n    \"complexes\": [\n      \"C4b2a (classical/lectin pathway C3 convertase)\"\n    ],\n    \"partners\": [\n      \"C4b\",\n      \"C1s\",\n      \"C3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (refusal — no on-target evidence) ---\n"}