7K66

Structure of Blood Coagulation Factor VIII in Complex with an Anti-C1 Domain Pathogenic Antibody Inhibitor

7K66 の概要

• エントリーDOI: 10.2210/pdb7k66/pdb
• 関連するPDBエントリー: 6MF0
• 分子名称: Coagulation factor VIII,Coagulation factor VIII,Coagulation factor VIII,Coagulation factor VIII, 2A9 heavy chain, 2A9 light chain, ... (10 entities in total)
• 機能のキーワード: antibody, inhibitor, blood clotting, blood clotting-immune system complex, blood clotting/immune system
• 由来する生物種: Sus scrofa (Pig); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 217290.01

構造登録者

Childers, K.C.,Gish, J.,Jarvis, L.,Peters, S.,Garrels, C.,Smith, I.W.,Spencer, H.T.,Spiegel, P.C. (登録日: 2020-09-18, 公開日: 2020-10-14, 最終更新日: 2023-10-18)

主引用文献

Gish, J.S.,Jarvis, L.,Childers, K.C.,Peters, S.C.,Garrels, C.S.,Smith, I.W.,Spencer, H.T.,Doering, C.B.,Lollar, P.,Spiegel, P.C.
Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor.
Blood, 137:2981-2986, 2021

PubMed Abstract: 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.

PubMed: 33529335
DOI: 10.1182/blood.2020008940

実験手法

X-RAY DIFFRACTION (3.92 Å)