2ZNK

Thrombin Inhibition

2ZNK の概要

• エントリーDOI: 10.2210/pdb2znk/pdb
• 関連するPDBエントリー: 2ZC9 2ZDA 2ZF0 2ZFP 2ZGB 2ZGX
• 関連するBIRD辞書のPRD_ID: PRD_000599
• 分子名称: Thrombin light chain, Thrombin heavy chain, Hirudin variant-1, ... (6 entities in total)
• 機能のキーワード: blood clotting, hydrolase inhibitor, acute phase, blood coagulation, cleavage on pair of basic residues, gamma-carboxyglutamic acid, glycoprotein, kringle, protease, serine protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase 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: P01050
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 35702.65

構造登録者

Baum, B.,Heine, A.,Klebe, G. (登録日: 2008-04-26, 公開日: 2009-04-14, 最終更新日: 2024-10-30)

主引用文献

Baum, B.,Muley, L.,Smolinski, M.,Heine, A.,Hangauer, D.,Klebe, G.
Non-additivity of functional group contributions in protein-ligand binding: a comprehensive study by crystallography and isothermal titration calorimetry.
J.Mol.Biol., 397:1042-1054, 2010

PubMed Abstract: Additivity of functional group contributions to protein-ligand binding is a very popular concept in medicinal chemistry as the basis of rational design and optimized lead structures. Most of the currently applied scoring functions for docking build on such additivity models. Even though the limitation of this concept is well known, case studies examining in detail why additivity fails at the molecular level are still very scarce. The present study shows, by use of crystal structure analysis and isothermal titration calorimetry for a congeneric series of thrombin inhibitors, that extensive cooperative effects between hydrophobic contacts and hydrogen bond formation are intimately coupled via dynamic properties of the formed complexes. The formation of optimal lipophilic contacts with the surface of the thrombin S3 pocket and the full desolvation of this pocket can conflict with the formation of an optimal hydrogen bond between ligand and protein. The mutual contributions of the competing interactions depend on the size of the ligand hydrophobic substituent and influence the residual mobility of ligand portions at the binding site. Analysis of the individual crystal structures and factorizing the free energy into enthalpy and entropy demonstrates that binding affinity of the ligands results from a mixture of enthalpic contributions from hydrogen bonding and hydrophobic contacts, and entropic considerations involving an increasing loss of residual mobility of the bound ligands. This complex picture of mutually competing and partially compensating enthalpic and entropic effects determines the non-additivity of free energy contributions to ligand binding at the molecular level.

PubMed: 20156458
DOI: 10.1016/j.jmb.2010.02.007

実験手法

X-RAY DIFFRACTION (1.8 Å)