Crystal structure of the human factor viii c2 domain in complex with murine 3e6 inhibitory antibody
Structure:
3e6 antibody fab heavy chain. Chain: a, e. 3e6 antibody fab light chain. Chain: b, f. Coagulation factor viii. Chain: m, g. Synonym: antihemophilic factor,ahf,procoagulant component. Engineered: yes
M.E.Wuerth
et al.
(2015).
Structure of the Human Factor VIII C2 Domain in Complex with the 3E6 Inhibitory Antibody.
Sci Rep,
5,
17216.
PubMed id: 26598467
DOI: 10.1038/srep17216
Structure of the Human Factor VIII C2 Domain in Complex with the 3E6 Inhibitory Antibody.
M.E.Wuerth,
R.K.Cragerud,
P.C.Spiegel.
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. 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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