Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody

Wuerth, Michelle E.; Cragerud, Rebecca K.; Spiegel, P. Clint

doi:10.1038/srep17216

Title: Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody

Journal Article · 23 November 2015 · Scientific Reports

DOI: https://doi.org/10.1038/srep17216 · OSTI ID:1241019

Wuerth, Michelle E. ^[1]; Cragerud, Rebecca K. ^[2]; Spiegel, P. Clint ^[2]

Western Washington Univ., Bellingham, WA (United States); Western Washington University
Western Washington Univ., Bellingham, WA (United States)

Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into “classical” and “non-classical” inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conserved when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Furthermore, understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents.

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Research Organization:: University of California

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1241019

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Vol. 5; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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