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1zhp
From Proteopedia
| 1zhp, resolution 2.70Å () | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||||
| Gene: | F11 (Homo sapiens) | ||||||||
| Activity: | Coagulation factor XIa, with EC number 3.4.21.27 | ||||||||
| Domains: | Tryp_SPc | ||||||||
| Related: | 1zhm, 1zhr, 1zjd | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Contents |
Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-K505 Mutant)
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.
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., Jin L, Pandey P, Babine RE, Weaver DT, Abdel-Meguid SS, Strickler JE, Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1418-25. Epub 2005, Sep 28. PMID:16204896
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Disease
Known disease associated with this structure: Factor XI deficiency, autosomal dominant OMIM:[264900], Factor XI deficiency, autosomal recessive OMIM:[264900]
About this Structure
1ZHP is a 1 chain structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Jin L, Pandey P, Babine RE, Weaver DT, Abdel-Meguid SS, Strickler JE. 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 D Biol Crystallogr. 2005 Oct;61(Pt 10):1418-25. Epub 2005, Sep 28. PMID:16204896 doi:10.1107/S0907444905024340
Page seeded by OCA on Mon Feb 16 10:23:31 2009
