5JS3

Thermolysin in complex with JC114.

Summary for 5JS3

• Entry DOI: 10.2210/pdb5js3/pdb
• Descriptor: Thermolysin, ZINC ION, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: hydrolase, metalloprotease, hydrolase inhibitor complex
• Biological source: Bacillus thermoproteolyticus
• Cellular location: Secreted: P00800
• Total number of polymer chains: 1
• Total formula weight: 35460.17

Authors

Krimmer, S.G.,Cramer, J.,Heine, A.,Klebe, G. (deposition date: 2016-05-07, release date: 2016-12-21, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.16 Å)