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PDBsum entry 7k66
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Blood clotting/immune system
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PDB id
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7k66
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Contents |
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1265 a.a.
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217 a.a.
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213 a.a.
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References listed in PDB file
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Key reference
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Title
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Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor.
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Authors
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J.S.Gish,
L.Jarvis,
K.C.Childers,
S.C.Peters,
C.S.Garrels,
I.W.Smith,
H.T.Spencer,
C.B.Doering,
P.Lollar,
P.C.Spiegel.
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Ref.
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Blood, 2021,
137,
2981-2986.
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PubMed id
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Abstract
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Antibody inhibitor development in hemophilia A represents the most significant
complication resulting from factor VIII (fVIII) replacement therapy. Recent
studies have demonstrated that epitopes present in the C1 domain contribute to a
pathogenic inhibitor response. In this study, we report the structure of a group
A anti-C1 domain inhibitor, termed 2A9, in complex with a B domain-deleted,
bioengineered fVIII construct (ET3i). The 2A9 epitope forms direct contacts to
the C1 domain at 3 different surface loops consisting of Lys2065-Trp2070,
Arg2150-Tyr2156, and Lys2110-Trp2112. Additional contacts are observed between
2A9 and the A3 domain, including the Phe1743-Tyr1748 loop and the N-linked
glycosylation at Asn1810. Most of the C1 domain loops in the 2A9 epitope also
represent a putative interface between fVIII and von Willebrand factor. Lastly,
the C2 domain in the ET3i:2A9 complex adopts a large, novel conformational
change, translocating outward from the structure of fVIII by 20 Å. This study
reports the first structure of an anti-C1 domain antibody inhibitor and the
first fVIII:inhibitor complex with a therapeutically active fVIII construct.
Further structural understanding of fVIII immunogenicity may result in the
development of more effective and safe fVIII replacement therapies.
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