1ZHP

Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-K505 Mutant)

1ZHP の概要

• エントリーDOI: 10.2210/pdb1zhp/pdb
• 関連するPDBエントリー: 1ZHM 1ZHR 1ZJD
• 分子名称: coagulation factor XI, BENZAMIDINE, GLUTATHIONE, ... (4 entities in total)
• 機能のキーワード: factor xi; benzamidine, hydrolase, blood clotting
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P03951
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27195.91

構造登録者

Jin, L.,Pandey, P.,Babine, R.E.,Weaver, D.T.,Abdel-Meguid, S.S.,Strickler, J.E. (登録日: 2005-04-26, 公開日: 2005-09-20, 最終更新日: 2023-08-23)

主引用文献

Jin, L.,Pandey, P.,Babine, R.E.,Weaver, D.T.,Abdel-Meguid, S.S.,Strickler, J.E.
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.,Sect.D, 61:1418-1425, 2005

PubMed 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.

PubMed: 16204896
DOI: 10.1107/S0907444905024340

実験手法

X-RAY DIFFRACTION (2.7 Å)