1MQ5

Crystal Structure of 3-chloro-N-[4-chloro-2-[[(4-chlorophenyl)amino]carbonyl]phenyl]-4-[(4-methyl-1-piperazinyl)methyl]-2-thiophenecarboxamide Complexed with Human Factor Xa

1MQ5 の概要

• エントリーDOI: 10.2210/pdb1mq5/pdb
• 関連するPDBエントリー: 1EZQ 1F0R 1F0S 1FJS 1QL7 1QL9 1mq6
• 分子名称: COAGULATION FACTOR X HEAVY CHAIN, COAGULATION FACTOR X LIGHT CHAIN, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: protein inhibitor complex, coagulation cofactor, protease, blood clotting
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P00742 P00742
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32660.37

構造登録者

Adler, M.,Whitlow, M. (登録日: 2002-09-13, 公開日: 2003-01-28, 最終更新日: 2024-11-06)

主引用文献

Adler, M.,Kochanny, M.J.,Bin, Y.,Rumennik, G.,Light, D.L.,Biancalana, S.,Whitlow, M.
Crystal Structures of Two Potent Nonamidine Inhibitors Bound to Factor Xa
Biochemistry, 41:15514-15523, 2002

PubMed Abstract: There has been intense interest in the development of factor Xa inhibitors for the treatment of thrombotic diseases. Our laboratory has developed a series of novel non-amidine inhibitors of factor Xa. This paper presents two crystal structures of compounds from this series bound to factor Xa. The first structure is derived from the complex formed between factor Xa and compound 1. Compound 1 was the first non-amidine factor Xa inhibitor from our lab that had measurable potency in an in vitro assay of anticoagulant activity. The second compound, 2, has a molar affinity for factor Xa (K(iapp)) of 7 pM and good bioavailability. The two inhibitors bind in an L-shaped conformation with a chloroaromatic ring buried deeply in the S1 pocket. The opposite end of these compounds contains a basic substituent that extends into the S4 binding site. A chlorinated phenyl ring bridges the substituents in the S1 and S4 pockets via amide linkers. The overall conformation is similar to the previously published structures for amidine-based inhibitors complexed with factor Xa. However, there are significant differences in the interactions between the inhibitor and the protein at the atomic level. Most notably, there is no group that forms a salt bridge with the carboxylic acid at the base of the S1 pocket (Asp189). Each inhibitor forms only one well-defined hydrogen bond to the protein. There are no direct charge-charge interactions. The results indicate that electrostatic interactions play a secondary role in the binding of these potent inhibitors.

PubMed: 12501180
DOI: 10.1021/bi0264061

実験手法

X-RAY DIFFRACTION (2.1 Å)