PDB 1ZHR deposited: 2005-04-26 modified: 2011-11-16
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.
Structure factors resolution 1.73 rfactor 0.183 rfree 0.202
DPI 0.47 theoretical min: 0.11
Related PDB Entries 1ZHM 1ZHP 2FDA

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

Cross References
Database source Identifier Description
PubMed 16204896 ABCRE6
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
1ZHR/0 1ZHR 0 monomer 0 1 1 2070