4AN6

Kuntiz type trypsin inhibitor with factor Xa inhibitory activity

4AN6 の概要

• エントリーDOI: 10.2210/pdb4an6/pdb
• 関連するPDBエントリー: 4AN7
• 分子名称: TRYPSIN INHIBITOR (2 entities in total)
• 機能のキーワード: kunitz type inhibitor, factor xa inhibitor, hydrolase inhibitor
• 由来する生物種: TAMARINDUS INDICA (TAMARIND)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 41204.43

構造登録者

Patil, D.N.,Kumar, P. (登録日: 2012-03-15, 公開日: 2012-11-07, 最終更新日: 2024-10-23)

主引用文献

Patil, D.N.,Chaudhary, A.,Sharma, A.K.,Tomar, S.,Kumar, P.
Structural Basis for Dual Inhibitory Role of Tamarind Kunitz Inhibitor (Tki) Against Factor Xa and Trypsin.
FEBS J., 279:4547-, 2012

PubMed Abstract: A Kunitz type dual inhibitor (TKI) of factor Xa (FXa) and trypsin was found in tamarind. It also shows prolongation of blood coagulation time. The deduced 185 amino acid sequence of TKI by cDNA cloning and sequence analysis revealed that it belongs to the Kunitz type soybean trypsin inhibitor (STI) family; however, it has a distorted Kunitz signature sequence due to insertion of Asn15 in the motif. TKI exhibited a competitive inhibitory activity against both FXa (K(i)  = 220 nm) and porcine pancreatic trypsin (K(i)  = 3.2 nm). The crystal structure of TKI shows a β-trefoil fold similar to Kunitz STI inhibitors; however, a distinct mobile reactive site, an inserted residue and loop β7β8 make it distinct from classical Kunitz inhibitors. The crystal structure of TKI-trypsin and a 3D model of TKI-FXa complex revealed that the distinct reactive site loop probably plays a role in dual inhibition. The reactive site of TKI interacts with an active site and two exosites (36 loop and autolysis loop) of FXa. Apart from Arg66 (P1), Arg64 (P3) is one of the most important residues responsible for the specificity of TKI towards FXa. Along with the reactive site loop (β4β5), loops β1 and β7β8 also interact with FXa and could further confer selectivity for FXa. We also present the role of inserted Asn15 in the stabilization of complexes. To the best of our knowledge, this is the first structure of FXa inhibitor belonging to the Kunitz type inhibitor family and its unique structural and sequence features make TKI a novel potent inhibitor.

PubMed: 23094997
DOI: 10.1111/FEBS.12042

実験手法

X-RAY DIFFRACTION (1.94 Å)