1FJS

CRYSTAL STRUCTURE OF THE INHIBITOR ZK-807834 (CI-1031) COMPLEXED WITH FACTOR XA

1FJS の概要

• エントリーDOI: 10.2210/pdb1fjs/pdb
• 関連するPDBエントリー: 1FAX 1HCG 1QB1 1QBN 1XKA 1XKB
• 分子名称: COAGULATION FACTOR XA, CALCIUM ION, CHLORIDE ION, ... (7 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: 33190.93

構造登録者

Adler, M.,Whitlow, M. (登録日: 2000-08-08, 公開日: 2000-10-04, 最終更新日: 2024-11-20)

主引用文献

Adler, M.,Davey, D.D.,Phillips, G.B.,Kim, S.H.,Jancarik, J.,Rumennik, G.,Light, D.R.,Whitlow, M.
Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa.
Biochemistry, 39:12534-12542, 2000

PubMed Abstract: Factor Xa plays a critical role in the formation of blood clots. This serine protease catalyzes the conversion of prothrombin to thrombin, the first joint step that links the intrinsic and extrinsic coagulation pathways. There is considerable interest in the development of factor Xa inhibitors for the intervention in thrombic diseases. This paper presents the structure of the inhibitor ZK-807834, also known as CI-1031, bound to factor Xa and provides the details of the protein purification and crystallization. Results from mass spectrometry indicate that the factor Xa underwent autolysis during crystallization and the first EGF-like domain was cleaved from the protein. The crystal structure of the complex shows that the amidine of ZK-807834 forms a salt bridge with Asp189 in the S1 pocket and the basic imidazoline fits snugly into the S4 site. The central pyridine ring provides a fairly rigid linker between these groups. This rigidity helps minimize entropic losses during binding. In addition, the structure reveals new interactions that were not found in the previous factor Xa/inhibitor complexes. ZK-807834 forms a strong hydrogen bond between an ionized 2-hydroxy group and Ser195 of factor Xa. There is also an aromatic ring-stacking interaction between the inhibitor and Trp215 in the S4 pocket. These interactions contribute to both the potency of this compound (K(I) = 0.11 nM) and the >2500-fold selectivity against homologous serine proteases such as trypsin.

PubMed: 11027132
DOI: 10.1021/bi001477q

実験手法

X-RAY DIFFRACTION (1.92 Å)