1ZHR: Crystal Structure Of The Catalytic Domain Of Coagulation Factor Xi In Complex With Benzamidine (S434a-T475a-C482s-K437a Mutant)

Citation:
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.
PDB ID: 1ZHRDownload
MMDB ID: 35120
PDB Deposition Date: 2005/4/26
Updated in MMDB: 2011/11
Experimental Method:
x-ray diffraction
Resolution: 1.73  Å
Source Organism:
Similar Structures:
Biological Unit for 1ZHR: monomeric; determined by author
Molecular Components in 1ZHR
Label Count Molecule
Protein (1 molecule)
1
Coagulation Factor XI(Gene symbol: F11)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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