ArticleFrontiers in immunology2021
Structure of Blood Coagulation Factor VIII in Complex With an Anti-C2 Domain Non-Classical, Pathogenic Antibody Inhibitor.
Article in Frontiers in immunology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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Who cites it
7 citing papers in PubMed, 8 citations in OpenAlex.
- Estimate of Numbers of Disulfide-Bonded Protein States.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Patient anti-FVIII drug antibodies bind preferentially to a subset of FVIII covalent states.Blood advances · 2025Article
- Biophysical characterization of blood coagulation factor VIII binding to lipid nanodiscs that mimic activated platelet surfaces.Journal of thrombosis and haemostasis : JTH · 2025Article
- Structural basis for inhibition of coagulation factor VIII reveals a shared antigenic hotspot on the C1 domain.Journal of thrombosis and haemostasis : JTH · 2024Article
- Genetics and Epigenetics in Acquired Hemophilia A: From Bench to Bedside.Current issues in molecular biology · 2024Review
- An intronic RNA element modulates Factor VIII exon-16 splicing.Nucleic acids research · 2024Article
- SAXS analysis of the intrinsic tenase complex bound to a lipid nanodisc highlights intermolecular contacts between factors VIIIa/IXa.Blood advances · 2022Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.