1xxf | pdb_00001xxf

Crystal Structure of the FXIa Catalytic Domain in Complex with Ecotin Mutant (EcotinP)

spinqualitylabelsall models 1xxf, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1xxf is a 4 chain structure with sequence from "bacillus_coli"_migula_1895 "bacillus coli" migula 1895 and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NA Related: 1xx9, 1xxd Gene: F11 (HUMAN), eco,eti ("Bacillus coli" Migula 1895) Activity: Coagulation factor XIa, with EC number 3.4.21.27 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [FA11_HUMAN] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:612416]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate. Function [FA11_HUMAN] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. [ECOT_ECOLI] General inhibitor of pancreatic serine proteases: inhibits chymotrypsin, trypsin, elastases, factor X, kallikrein as well as a variety of other proteases. The strength of inhibition does not appear to be correlated with a particular protease specificity.[HAMAP-Rule:MF_00706] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ecotin Factor XIa

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