3P6Z
Structural basis of thrombin mediated factor V activation: essential role of the hirudin-like sequence Glu666-Glu672 for processing at the heavy chain-B domain junction
Summary for 3P6Z
Entry DOI | 10.2210/pdb3p6z/pdb |
Related | 1DX5 1E0F 1NU7 1PPB 2PW8 3LU9 3P70 |
Related PRD ID | PRD_000020 |
Descriptor | Thrombin light chain, Thrombin heavy chain, Coagulation factor V, ... (9 entities in total) |
Functional Keywords | trypsin-like serine proteinase, blood coagulation, n-glycosylation, blood plasma, ppack, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
Biological source | Homo sapiens (human) More |
Total number of polymer chains | 6 |
Total formula weight | 86319.21 |
Authors | Corral-Rodriguez, M.A.,Bock, P.E.,Hernandez-Carvajal, E.,Gutierrez-Gallego, R.,Fuentes-Prior, P. (deposition date: 2010-10-11, release date: 2011-06-15, Last modification date: 2024-10-30) |
Primary citation | Corral-Rodriguez, M.A.,Bock, P.E.,Hernandez-Carvajal, E.,Gutierrez-Gallego, R.,Fuentes-Prior, P. Structural basis of thrombin-mediated factor V activation: the Glu666-Glu672 sequence is critical for processing at the heavy chain-B domain junction. Blood, 117:7164-7173, 2011 Cited by PubMed Abstract: Thrombin-catalyzed activation of coagulation factor V (FV) is an essential positive feedback reaction within the blood clotting system. Efficient processing at the N- (Arg(709)-Ser(710)) and C-terminal activation cleavage sites (Arg(1545)-Ser(1546)) requires initial substrate interactions with 2 clusters of positively charged residues on the proteinase surface, exosites I and II. We addressed the mechanism of activation of human factor V (FV) using peptides that cover the entire acidic regions preceding these cleavage sites, FV (657-709)/ (FVa2) and FV(1481-1545)/(FVa3). FVa2 appears to interact mostly with exosite I, while both exosites are involved in interactions with the C-terminal linker. The 1.7-Å crystal structure of irreversibly inhibited thrombin bound to FVa2 unambiguously reveals docking of FV residues Glu(666)-Glu(672) to exosite I. These findings were confirmed in a second, medium-resolution structure of FVa2 bound to the benzamidine-inhibited proteinase. Our results suggest that the acidic A2-B domain linker is involved in major interactions with thrombin during cofactor activation, with its more N-terminal hirudin-like sequence playing a critical role. Modeling experiments indicate that FVa2, and likely also FVa3, wrap around thrombin in productive thrombin·FV complexes that cover a large surface of the activator to engage the active site. PubMed: 21555742DOI: 10.1182/blood-2010-10-315309 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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