7KWO

rFVIIIFc-VWF-XTEN (BIVV001)

Summary for 7KWO

• Entry DOI: 10.2210/pdb7kwo/pdb
• EMDB information: 23057
• Descriptor: Coagulation factor FVIII-Fc-XTEN, von Willebrand factor-XTEN-Fc, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: complex, hemophilia, fviii, vwf, blood clotting
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 399383.20

Authors

Fuller, J.R.,Batchelor, J.D. (deposition date: 2020-12-01, release date: 2021-03-03, Last modification date: 2024-10-16)

Primary citation

Fuller, J.R.,Knockenhauer, K.E.,Leksa, N.C.,Peters, R.T.,Batchelor, J.D.
Molecular determinants of the factor VIII/von Willebrand factor complex revealed by BIVV001 cryo-electron microscopy.
Blood, 137:2970-2980, 2021

PubMed Abstract: Interaction of factor VIII (FVIII) with von Willebrand factor (VWF) is mediated by the VWF D'D3 domains and thrombin-mediated release is essential for hemostasis after vascular injury. VWF-D'D3 mutations resulting in loss of FVIII binding are the underlying cause of von Willebrand disease (VWD) type 2N. Furthermore, the FVIII-VWF interaction has significant implications for the development of therapeutics for bleeding disorders, particularly hemophilia A, in which endogenous VWF clearance imposes a half-life ceiling on replacement FVIII therapy. To understand the structural basis of FVIII engagement by VWF, we solved the structure of BIVV001 by cryo-electron microscopy to 2.9 Å resolution. BIVV001 is a bioengineered clinical-stage FVIII molecule for the treatment of hemophilia A. In BIVV001, VWF-D'D3 is covalently linked to an Fc domain of a B domain-deleted recombinant FVIII (rFVIII) Fc fusion protein, resulting in a stabilized rFVIII/VWF-D'D3 complex. Our rFVIII/VWF structure resolves BIVV001 architecture and provides a detailed spatial understanding of previous biochemical and clinical observations related to FVIII-VWF engagement. Notably, the FVIII acidic a3 peptide region (FVIII-a3), established as a critical determinant of FVIII/VWF complex formation, inserts into a basic groove formed at the VWF-D'/rFVIII interface. Our structure shows direct interaction of sulfated Y1680 in FVIII-a3 and VWF-R816 that, when mutated, leads to severe hemophilia A or VWD type 2N, respectively. These results provide insight on this key coagulation complex, explain the structural basis of many hemophilia A and VWD type 2N mutations, and inform studies to further elucidate how VWF dissociates rapidly from FVIII upon activation.

PubMed: 33569592
DOI: 10.1182/blood.2020009197

Experimental method

ELECTRON MICROSCOPY (2.9 Å)