3HNY

Factor VIII Trp2313-His2315 segment is involved in membrane binding as shown by crystal structure of complex between factor VIII C2 domain and an inhibitor

3HNY の概要

• エントリーDOI: 10.2210/pdb3hny/pdb
• 分子名称: Coagulation factor VIII (2 entities in total)
• 機能のキーワード: blood clotting, acute phase, blood coagulation, calcium, disease mutation, disulfide bond, glycoprotein, hemophilia, metal-binding, pharmaceutical, polymorphism, secreted, sulfation
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted, extracellular space: P00451
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18029.56

構造登録者

Liu, Z.,Yuan, C. (登録日: 2009-06-01, 公開日: 2010-01-19, 最終更新日: 2024-11-20)

主引用文献

Liu, Z.,Lin, L.,Yuan, C.,Nicolaes, G.A.,Chen, L.,Meehan, E.J.,Furie, B.,Furie, B.,Huang, M.
Trp2313-His2315 of factor VIII C2 domain is involved in membrane binding: structure of a complex between the C2 domain and an inhibitor of membrane binding.
J.Biol.Chem., 285:8824-8829, 2010

PubMed Abstract: Factor VIII (FVIII) plays a critical role in blood coagulation by forming the tenase complex with factor IXa and calcium ions on a membrane surface containing negatively charged phospholipids. The tenase complex activates factor X during blood coagulation. The carboxyl-terminal C2 domain of FVIII is the main membrane-binding and von Willebrand factor-binding region of the protein. Mutations of FVIII cause hemophilia A, whereas elevation of FVIII activity is a risk factor for thromboembolic diseases. The C2 domain-membrane interaction has been proposed as a target of intervention for regulation of blood coagulation. A number of molecules that interrupt FVIII or factor V (FV) binding to cell membranes have been identified through high throughput screening or structure-based design. We report crystal structures of the FVIII C2 domain under three new crystallization conditions, and a high resolution (1.15 A) crystal structure of the FVIII C2 domain bound to a small molecular inhibitor. The latter structure shows that the inhibitor binds to the surface of an exposed beta-strand of the C2 domain, Trp(2313)-His(2315). This result indicates that the Trp(2313)-His(2315) segment is an important constituent of the membrane-binding motif and provides a model to understand the molecular mechanism of the C2 domain membrane interaction.

PubMed: 20089867
DOI: 10.1074/jbc.M109.080168

実験手法

X-RAY DIFFRACTION (1.07 Å)