1XXF

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

1XXF の概要

• エントリーDOI: 10.2210/pdb1xxf/pdb
• 関連するPDBエントリー: 1XX9 1XXD
• 分子名称: Coagulation factor XI, Ecotin, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: fxia; catalytic domain; serine protease; ecotin; substrate-like interaction, blood clotting-hydrolase inhibitor complex, blood clotting/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P03951; Periplasm: P23827
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 86136.15

構造登録者

Jin, L.,Pandey, P.,Babine, R.E.,Gorga, J.C.,Seidl, K.J.,Gelfand, E.,Weaver, D.T.,Abdel-Meguid, S.S.,Strickler, J.E. (登録日: 2004-11-04, 公開日: 2004-11-16, 最終更新日: 2023-08-23)

主引用文献

Jin, L.,Pandey, P.,Babine, R.E.,Gorga, J.C.,Seidl, K.J.,Gelfand, E.,Weaver, D.T.,Abdel-Meguid, S.S.,Strickler, J.E.
Crystal Structures of the FXIa Catalytic Domain in Complex with Ecotin Mutants Reveal Substrate-like Interactions
J.Biol.Chem., 280:4704-4712, 2005

PubMed Abstract: 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.

PubMed: 15545266
DOI: 10.1074/jbc.M411309200

実験手法

X-RAY DIFFRACTION (2.6 Å)