1DWC

CRYSTALLOGRAPHIC ANALYSIS AT 3.0-ANGSTROMS RESOLUTION OF THE BINDING TO HUMAN THROMBIN OF FOUR ACTIVE SITE-DIRECTED INHIBITORS

1DWC の概要

• エントリーDOI: 10.2210/pdb1dwc/pdb
• 関連するPDBエントリー: 1DWB 1DWD 1DWE
• 関連するBIRD辞書のPRD_ID: PRD_000452
• 分子名称: ALPHA-THROMBIN (SMALL SUBUNIT), ALPHA-THROMBIN (LARGE SUBUNIT), HIRUDIN IIIA, ... (5 entities in total)
• 機能のキーワード: serine proteinase, hydrolase-hyrolase inhibitor complex, hydrolase/hyrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted, extracellular space: P00734 P00734; Secreted: P28508
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 35797.86

構造登録者

Banner, D.W.,Hadvary, P. (登録日: 1992-08-19, 公開日: 1994-01-31, 最終更新日: 2024-11-20)

主引用文献

Banner, D.W.,Hadvary, P.
Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors.
J.Biol.Chem., 266:20085-20093, 1991

PubMed Abstract: The mode of binding of four active-site directed inhibitors to human thrombin has been determined by x-ray crystallographic analysis. The inhibitors studied are benzamidine, PPACK, NAPAP, and MD-805, of which the last three are compounds evolved specifically to inhibit thrombin. Crystal structures were determined in the presence of both the inhibitor and the undecapeptide [des-amino Asp55]hirudin(55-65) which binds distant from the active site. Despite having significantly different chemical structures, NAPAP and MD-805 bind to thrombin in a very similar "inhibitor binding mode" which is not that expected by direct analogy with the binding of substrate. Both inhibitors bind to thrombin in a similar way as to trypsin, but thrombin has an extra loop, the "Tyr-Pro-Pro-Trp loop," not present in trypsin, which gives further binding interactions and is seen to move somewhat to accommodate binding of the different inhibitors. The fact that NAPAP and MD-805 require different stereochemistry for potent inhibition is demonstrated, and its structural basis clarified. The wealth of data on analogs and variants of these lead compounds is shown to be compatible with this inhibitor binding mode.

PubMed: 1939071

実験手法

X-RAY DIFFRACTION (3 Å)