ArticleJournal of thrombosis and haemostasis : JTH2020
The 3.2 Å structure of a bioengineered variant of blood coagulation factor VIII indicates two conformations of the C2 domain.
Article in Journal of thrombosis and haemostasis : JTH, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Decoding full-length factor VIII through the structural and functional lens of its B domain.Blood vessels, thrombosis & hemostasis · 2026Article
- Structural basis for membrane binding by coagulation factors V and VIII and their specificity for phosphatidylserine-containing membranes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- 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
- Analyzing 6211 unique variants in the upgraded interactive FVIII web database reveals novel insights into hemophilia A.Blood vessels, thrombosis & hemostasis · 2025Article
- Atomistic Mechanism of Lipid Membrane Binding for Blood Coagulation Factor VIII with Molecular Dynamics Simulations on a Microsecond Time Scale.The journal of physical chemistry. B · 2025Article
- Persistent splenic-derived IgMs preferentially recognize factor VIII A2 and C2 domain epitopes but do not alter antibody production.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
- The combination of Asp519Val/Glu665Val and Lys1813Ala mutations in FVIII markedly increases coagulation potential.Blood advances · 2024Article
- Lactadherin's Multistate Binding Predicts Stable Membrane-Bound Conformations of Factors V and VIII's C Domains.Biochemistry · 2023Article
- Molecular engineering of cyclic azobenzene-peptide hybrid ligands for the purification of human blood Factor VIII via photo-affinity chromatography.Advanced functional materials · 2023Article
- A graph-based machine learning framework identifies critical properties of FVIII that lead to hemophilia A.Frontiers in bioinformatics · 2023Article
- SAXS analysis of the intrinsic tenase complex bound to a lipid nanodisc highlights intermolecular contacts between factors VIIIa/IXa.Blood advances · 2022Article
- Stable binding to phosphatidylserine-containing membranes requires conserved arginine residues in tandem C domains of blood coagulation factor VIII.Frontiers in molecular biosciences · 2022Article
- Uncovering Membrane-Bound Models of Coagulation Factors by Combined Experimental and Computational Approaches.Thrombosis and haemostasis · 2021Review
- Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.Research and practice in thrombosis and haemostasis · 2021Review
- Protein residue network analysis reveals fundamental properties of the human coagulation factor VIII.Scientific reports · 2021Article
- Article
- Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor.Blood · 2021Article
- Prediction of hemophilia A severity using a small-input machine-learning framework.NPJ systems biology and applications · 2021Article
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundCoagulation factor VIII represents one of the oldest protein-based therapeutics, serving as an effective hemophilia A treatment for half a century. Optimal treatment consists of repeated intravenous infusions of blood coagulation factor VIII (FVIII) per week for life. Despite overall treatment success, significant limitations remain, including treatment invasiveness, duration, immunogenicity, and cost. These issues have inspired research into the development of bioengineered FVIII products and gene therapies.
objectivesTo structurally characterize a bioengineered construct of FVIII, termed ET3i, which is a human/porcine chimeric B domain-deleted heterodimer with improved expression and slower A2 domain dissociation following proteolytic activation by thrombin.
methodsThe structure of ET3i was characterized with X-ray crystallography and tandem mass spectrometry-based glycoproteomics.
resultsHere, we report the 3.2 Å crystal structure of ET3i and characterize the distribution of N-linked glycans with LC-MS/MS glycoproteomics. This structure shows remarkable conservation with the human FVIII protein and provides a detailed view of the interface between the A2 domain and the remaining FVIII structure. With two FVIII molecules in the crystal, we observe two conformations of the C2 domain relative to the remaining FVIII structure. The improved model and stereochemistry of ET3i served as a scaffold to generate an improved, refined structure of human FVIII. With the original datasets at 3.7 Å and 4.0 Å resolution, this new structure resulted in improved refinement statistics.
conclusionsThese improved structures yield a more confident model for next-generation engineering efforts to develop FVIII therapeutics with longer half-lives, higher expression levels, and lower immunogenicity.
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