Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody
Abstract
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.
- Authors:
-
- Western Washington Univ., Bellingham, WA (United States)
- Publication Date:
- Research Org.:
- Univ. of California (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1241019
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Volume: 5; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; coagulation system; X-ray crystallography
Citation Formats
Wuerth, Michelle E., Cragerud, Rebecca K., and Spiegel, P. Clint. Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody. United States: N. p., 2015.
Web. doi:10.1038/srep17216.
Wuerth, Michelle E., Cragerud, Rebecca K., & Spiegel, P. Clint. Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody. United States. https://doi.org/10.1038/srep17216
Wuerth, Michelle E., Cragerud, Rebecca K., and Spiegel, P. Clint. Tue .
"Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody". United States. https://doi.org/10.1038/srep17216. https://www.osti.gov/servlets/purl/1241019.
@article{osti_1241019,
title = {Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody},
author = {Wuerth, Michelle E. and Cragerud, Rebecca K. and Spiegel, P. Clint},
abstractNote = {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.},
doi = {10.1038/srep17216},
journal = {Scientific Reports},
number = ,
volume = 5,
place = {United States},
year = {Tue Nov 24 00:00:00 EST 2015},
month = {Tue Nov 24 00:00:00 EST 2015}
}
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