{"doi":"10.3389/fimmu.2021.697602","title":"Structure of Blood Coagulation Factor VIII in Complex With an Anti-C2 Domain Non-Classical, Pathogenic Antibody Inhibitor","abstract":"Factor VIII (fVIII) is a procoagulant protein that binds to activated factor IX (fIXa) on platelet surfaces to form the intrinsic tenase complex. Due to the high immunogenicity of fVIII, generation of antibody inhibitors is a common occurrence in patients during hemophilia A treatment and spontaneously occurs in acquired hemophilia A patients. Non-classical antibody inhibitors, which block fVIII activation by thrombin and formation of the tenase complex, are the most common anti-C2 domain pathogenic inhibitors in hemophilia A murine models and have been identified in patient plasmas. In this study, we report on the X-ray crystal structure of a B domain-deleted bioengineered fVIII bound to the non-classical antibody inhibitor, G99. While binding to G99 does not disrupt the overall domain architecture of fVIII, the C2 domain undergoes an ~8 Å translocation that is concomitant with breaking multiple domain-domain interactions. Analysis of normalized B-factor values revealed several solvent-exposed loops in the C1 and C2 domains which experience a decrease in thermal motion in the presence of inhibitory antibodies. These results enhance our understanding on the structural nature of binding non-classical inhibitors and provide a structural dynamics-based rationale for cooperativity between anti-C1 and anti-C2 domain inhibitors.","journal":"Frontiers in Immunology","year":2021,"id":199193,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":715474,"name":"Shaun C. Peters","orcid":"0000-0002-5997-9685","position":1,"is_corresponding":false},{"id":716187,"name":"Joseph S. Gish","orcid":null,"position":2,"is_corresponding":false},{"id":775648,"name":"Celena Wilson","orcid":null,"position":3,"is_corresponding":false},{"id":380171,"name":"H. Trent Spencer","orcid":"0000-0001-8062-2202","position":4,"is_corresponding":false},{"id":380170,"name":"Christopher B. Doering","orcid":"0000-0002-5662-0060","position":5,"is_corresponding":false},{"id":409323,"name":"Pete Lollar","orcid":"0000-0002-1206-8104","position":6,"is_corresponding":false},{"id":715476,"name":"Paul Spiegel","orcid":"0000-0001-7982-5424","position":7,"is_corresponding":false},{"id":715473,"name":"Kenneth Childers","orcid":"0000-0003-0472-7859","position":8,"is_corresponding":false},{"id":775647,"name":"Estelle K. Ronayne","orcid":null,"position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:50:36.595945Z","pmid":"34177966","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}