PDB |
1ZHR deposited: 2005-04-26 modified: 2011-11-16 |
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Title |
Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-C482S-K437A Mutant) |
Authors |
Abdel-Meguid, S.S., Babine, R.E., Jin, L., Pandey, P., Strickler, J.E., Weaver, D.T. |
Method |
X-RAY DIFFRACTION |
Structure factors |
resolution 1.73 rfactor 0.183 rfree 0.202 |
DPI |
0.47
theoretical min: 0.11
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Related PDB Entries |
1ZHM
1ZHP
2FDA
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Citations |
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.
Acta Crystallogr.,Sect.D 2005 Oct; 61(Pt 10):1418-1425 doi:10.1107/S0907444905024340
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