6TDT

Thrombin in Complex with a D-DiPhe-Pro-p-pyridine derivative

6TDT の概要

• エントリーDOI: 10.2210/pdb6tdt/pdb
• 分子名称: Prothrombin, Hirudin variant-2, PHOSPHATE ION, ... (9 entities in total)
• 機能のキーワード: coagulation, blood clotting, convertion of fibrinogen to fibrin, blood clotting inhibitor, thrombin inhibitor, preorganization, glycosylation, blood, hydrolase
• 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: 36237.10

構造登録者

Ngo, K.,Heine, A.,Klebe, G. (登録日: 2019-11-10, 公開日: 2020-05-13, 最終更新日: 2024-11-20)

主引用文献

Ngo, K.,Collins-Kautz, C.,Gerstenecker, S.,Wagner, B.,Heine, A.,Klebe, G.
Protein-Induced Change in Ligand Protonation during Trypsin and Thrombin Binding: Hint on Differences in Selectivity Determinants of Both Proteins?
J.Med.Chem., 63:3274-3289, 2020

PubMed Abstract: Trypsin and thrombin, structurally similar serine proteases, recognize different substrates; thrombin cleaves after Arg, whereas trypsin cleaves after Lys/Arg. Both recognize basic substrate headgroups via Asp189 at the bottom of the S1 pocket. By crystallography and isothermal titration calorimetry (ITC), we studied a series of d-Phe/d-DiPhe-Pro-(amino)pyridines. Identical ligand pairs show the same binding poses. Surprisingly, one ligand binds to trypsin in protonated state and to thrombin in unprotonated state at P1 along with differences in the residual solvation pattern. While trypsin binding is mediated by an ordered water molecule, in thrombin, water is scattered over three hydration sites. Although having highly similar S1 pockets, our results suggest different electrostatic properties of Asp189 possibly contributing to the selectivity determinant. Thrombin binds a specific Na ion next to Asp189, which is absent in trypsin. The electrostatic properties across the S1 pocket are further attenuated by charged Glu192 at the rim of S1 in thrombin, which is replaced by uncharged Gln192 in trypsin.

PubMed: 32011145
DOI: 10.1021/acs.jmedchem.9b02061

実験手法

X-RAY DIFFRACTION (1.53 Å)