1ZHP
Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-K505 Mutant)
Summary for 1ZHP
| Entry DOI | 10.2210/pdb1zhp/pdb |
| Related | 1ZHM 1ZHR 1ZJD |
| Descriptor | coagulation factor XI, BENZAMIDINE, GLUTATHIONE, ... (4 entities in total) |
| Functional Keywords | factor xi; benzamidine, hydrolase, blood clotting |
| Biological source | Homo sapiens (human) |
| Cellular location | Secreted: P03951 |
| Total number of polymer chains | 1 |
| Total formula weight | 27195.91 |
| Authors | Jin, L.,Pandey, P.,Babine, R.E.,Weaver, D.T.,Abdel-Meguid, S.S.,Strickler, J.E. (deposition date: 2005-04-26, release date: 2005-09-20, Last modification date: 2023-08-23) |
| Primary citation | Jin, L.,Pandey, P.,Babine, R.E.,Weaver, D.T.,Abdel-Meguid, S.S.,Strickler, J.E. Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitors. Acta Crystallogr.,Sect.D, 61:1418-1425, 2005 Cited by PubMed Abstract: Activated factor XI (FXIa) is a key enzyme in the amplification phase of the blood-coagulation cascade. Thus, a selective FXIa inhibitor may have lesser bleeding liabilities and provide a safe alternative for antithrombosis therapy to available drugs on the market. In a previous report, the crystal structures of the catalytic domain of FXIa (rhFXI(370-607)) in complex with various ecotin mutants have been described. However, ecotin forms a matrix-like interaction with rhFXI(370-607) and is impossible to displace with small-molecule inhibitors; ecotin crystals are therefore not suitable for iterative structure-based ligand design. In addition, rhFXI(370-607) did not crystallize in the presence of small-molecule ligands. In order to obtain the crystal structure of rhFXI(370-607) with a weak small-molecule ligand, namely benzamidine, several rounds of surface-residue mutation were implemented to promote crystal formation of rhFXI(370-607). A quadruple mutant of rhFXI(370-607) (rhFXI(370-607)-S434A,T475A,C482S,K437A) readily crystallized in the presence of benzamidine. The benzamidine in the preformed crystals was easily exchanged with other FXIa small-molecule inhibitors. These crystals have facilitated the structure-based design of small-molecule FXIa inhibitors. PubMed: 16204896DOI: 10.1107/S0907444905024340 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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