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
Summary for 3HNY
| Entry DOI | 10.2210/pdb3hny/pdb |
| Descriptor | Coagulation factor VIII (2 entities in total) |
| Functional Keywords | blood clotting, acute phase, blood coagulation, calcium, disease mutation, disulfide bond, glycoprotein, hemophilia, metal-binding, pharmaceutical, polymorphism, secreted, sulfation |
| Biological source | Homo sapiens (human) |
| Cellular location | Secreted, extracellular space: P00451 |
| Total number of polymer chains | 1 |
| Total formula weight | 18029.56 |
| Authors | |
| Primary citation | 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 Cited by 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: 20089867DOI: 10.1074/jbc.M109.080168 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.07 Å) |
Structure validation
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