5JSS

Thermolysin in complex with JC149.

5JSS の概要

• エントリーDOI: 10.2210/pdb5jss/pdb
• 分子名称: Thermolysin, ZINC ION, CALCIUM ION, ... (7 entities in total)
• 機能のキーワード: hydrolase, metalloprotease, hydrolase inhibitor complex
• 由来する生物種: Bacillus thermoproteolyticus
• 細胞内の位置: Secreted: P00800
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35460.17

構造登録者

Krimmer, S.G.,Cramer, J.,Heine, A.,Klebe, G. (登録日: 2016-05-09, 公開日: 2016-12-21, 最終更新日: 2024-01-10)

主引用文献

Krimmer, S.G.,Cramer, J.,Betz, M.,Fridh, V.,Karlsson, R.,Heine, A.,Klebe, G.
Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands.
J. Med. Chem., 59:10530-10548, 2016

PubMed Abstract: A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S' pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water molecules resulted in an enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, we optimized the series by designing tailored P' substituents to improve and further stabilize the surface water network. MD simulations were applied to predict the putative water pattern around the bound ligands. Subsequently, the inhibitors were synthesized and characterized by high-resolution crystallography, microcalorimetry, and surface plasmon resonance. One of the designed inhibitors established the most pronounced water network of all inhibitors tested so far, composed of several fused water polygons, and showed 50-fold affinity enhancement with respect to the original methylated parent ligand. Notably, the inhibitor forming the most perfect water network also showed significantly prolonged residence time compared to the other tested inhibitors.

PubMed: 27933956
DOI: 10.1021/acs.jmedchem.6b00998

実験手法

X-RAY DIFFRACTION (1.19 Å)