5N2X

Thermolysin in complex with inhibitor JC272

5N2X の概要

• エントリーDOI: 10.2210/pdb5n2x/pdb
• 分子名称: Thermolysin, ZINC ION, CALCIUM ION, ... (7 entities in total)
• 機能のキーワード: inhibitor, phosphonamidate, protease, hydrolase
• 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: 35411.10

構造登録者

Cramer, J.,Krimmer, S.G.,Heine, A.,Klebe, G. (登録日: 2017-02-08, 公開日: 2017-06-21, 最終更新日: 2024-01-17)

主引用文献

Cramer, J.,Krimmer, S.G.,Heine, A.,Klebe, G.
Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors.
J. Med. Chem., 60:5791-5799, 2017

PubMed Abstract: In lead optimization, open, solvent-exposed protein pockets are often disregarded as prospective binding sites. Because of bulk-solvent proximity, researchers are instead enticed to attach charged polar groups at inhibitor scaffolds to improve solubility and pharmacokinetic properties. It is rarely considered that solvent effects from water reorganization in the first hydration shell of protein-ligand complexes can have a significant impact on binding. We investigate the thermodynamic fingerprint of thermolysin inhibitors featuring terminal charged ammonium groups that are gradually pulled from a distal, solvent-exposed position into the flat, bowl-shaped S' pocket. Even for the most remote attachment, costs for partial desolvation of the polar group next to the protein-solvent interface are difficult to compensate by interactions with the protein or surrounding water molecules. Through direct comparison with hydrophobic analogues, a significant 180-fold affinity loss was recorded, which questions popular strategies to attach polar ligand-solubilizing groups at the exposed terminus of substituents accommodated in flat open pockets.

PubMed: 28590130
DOI: 10.1021/acs.jmedchem.7b00490

実験手法

X-RAY DIFFRACTION (1.209 Å)