3RMO

Human Thrombin in complex with MI004

3RMO の概要

• エントリーDOI: 10.2210/pdb3rmo/pdb
• 関連するPDBエントリー: 3RLW 3RLY 3RM0 3RM2 3RML 3RMM 3RMN
• 関連するBIRD辞書のPRD_ID: PRD_001005
• 分子名称: Thrombin Light Chain, Thrombin Heavy Chain, Hirudin variant-2, ... (9 entities in total)
• 機能のキーワード: serine protease, kringle, hydrolase, blood coagulation, blood clotting, convertion of fibrinogen, hirudin, glycosylation, blood, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 36660.94

構造登録者

Biela, A.,Heine, A.,Klebe, G. (登録日: 2011-04-21, 公開日: 2012-04-25, 最終更新日: 2024-10-30)

主引用文献

Biela, A.,Sielaff, F.,Terwesten, F.,Heine, A.,Steinmetzer, T.,Klebe, G.
Ligand binding stepwise disrupts water network in thrombin: enthalpic and entropic changes reveal classical hydrophobic effect
J.Med.Chem., 55:6094-6110, 2012

PubMed Abstract: Well-ordered water molecules are displaced from thrombin's hydrophobic S3/4-pocket by P3-varied ligands (Gly, d-Ala, d-Val, d-Leu to d-Cha with increased hydrophobicity and steric requirement). Two series with 2-(aminomethyl)-5-chlorobenzylamide and 4-amidinobenzylamide at P1 were examined by ITC and crystallography. Although experiencing different interactions in S1, they display almost equal potency. For both scaffolds the terminal benzylsulfonyl substituent differs in binding, whereas the increasingly bulky P3-groups address S3/4 pocket similarly. Small substituents leave the solvation pattern unperturbed as found in the uncomplexed enzyme while increasingly larger ones stepwise displace the waters. Medium-sized groups show patterns with partially occupied waters. The overall 40-fold affinity enhancement correlates with water displacement and growing number of van der Waals contacts and is mainly attributed to favorable entropy. Both Gly derivatives deviate from the series and adopt different binding modes. Nonetheless, their thermodynamic signatures are virtually identical with the homologous d-Ala derivatives. Accordingly, unchanged thermodynamic profiles are no reliable indicator for conserved binding modes.

PubMed: 22612268
DOI: 10.1021/jm300337q

実験手法

X-RAY DIFFRACTION (1.4 Å)