1xx9
From Proteopedia
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Crystal Structure of the FXIa Catalytic Domain in Complex with EcotinM84R
Contents |
Overview
Thrombosis can lead to life-threatening conditions such as acute, myocardial infarction, pulmonary embolism, and stroke. Although commonly, used anti-coagulant drugs, such as low molecular weight heparin and, warfarin, are effective, they carry a significant risk of inducing severe, bleeding complications, and there is a need for safer drugs. Activated, Factor XI (FXIa) is a key enzyme in the amplification phase of the, coagulation cascade. Anti-human FXI antibody significantly reduces, thrombus growth in a baboon thrombosis model without bleeding problems, (Gruber, A., and Hanson, S. R. (2003) Blood 102, 953-955). Therefore, FXIa, is a potential target for anti-thrombosis therapy. To determine the, structure of FXIa, we derived a recombinant catalytic domain of FXI, consisting of residues 370-607 (rhFXI370-607). Here we report the first, crystal structure of rhFXI370-607 in complex with a substitution mutant of, ecotin, a panserine protease protein inhibitor secreted by Escherichia, coli, to 2.2 A resolution. The presence of ecotin not only assisted in the, crystallization of the enzyme but also revealed unique structural features, in the active site of FXIa. Subsequently, the sequence from P5 to P2' in, ecotin was mutated to the FXIa substrate sequence, and the structures of, the rhFXI370-607-ecotin mutant complexes were determined. These structures, provide us with an understanding of substrate binding interactions of, FXIa, the structural information essential for the structure-based design, of FXIa-selective inhibitors.
Disease
Known diseases associated with this structure: Factor XI deficiency, autosomal dominant OMIM:[264900], Factor XI deficiency, autosomal recessive OMIM:[264900]
About this Structure
1XX9 is a Protein complex structure of sequences from Escherichia coli and Homo sapiens with NAG as ligand. Active as Coagulation factor XIa, with EC number 3.4.21.27 Full crystallographic information is available from OCA.
Reference
Crystal structures of the FXIa catalytic domain in complex with ecotin mutants reveal substrate-like interactions., Jin L, Pandey P, Babine RE, Gorga JC, Seidl KJ, Gelfand E, Weaver DT, Abdel-Meguid SS, Strickler JE, J Biol Chem. 2005 Feb 11;280(6):4704-12. Epub 2004 Nov 15. PMID:15545266
Page seeded by OCA on Mon Nov 12 20:12:13 2007
