3T73

Thermolysin In Complex With UBTLN22

Summary for 3T73

• Entry DOI: 10.2210/pdb3t73/pdb
• Related: 3ELF 3T74 3T87 3T8C 3T8D 3T8F 3T8G 3T8H 4TMN 5TMN
• Related PRD ID: PRD_000980
• Descriptor: Thermolysin, N-[(S)-({[(benzyloxy)carbonyl]amino}methyl)(hydroxy)phosphoryl]-N-methyl-L-leucinamide, GLYCEROL, ... (7 entities in total)
• Functional Keywords: protease, metalloprotease, hydrolysis of peptide bonds, phosphoramidon, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Bacillus thermoproteolyticus
• Cellular location: Secreted: P00800
• Total number of polymer chains: 1
• Total formula weight: 35638.33

Authors

Biela, A.,Heine, A.,Klebe, G. (deposition date: 2011-07-29, release date: 2012-08-01, Last modification date: 2023-09-13)

Primary citation

Biela, A.,Betz, M.,Heine, A.,Klebe, G.
Water makes the difference: rearrangement of water solvation layer triggers non-additivity of functional group contributions in protein-ligand binding.
Chemmedchem, 7:1423-1434, 2012

PubMed Abstract: The binding of four congeneric peptide-like thermolysin inhibitors has been studied by high-resolution crystal structure analysis and isothermal titration calorimetry. The ligands differ only by a terminal carboxylate and/or methyl group. A surprising non-additivity of functional group contributions for the carboxylate and/or methyl groups is detected. Adding the methyl first and then the carboxylate group results in a small Gibbs free energy increase and minor enthalpy/entropy partitioning for the first modification, whereas the second involves a strong affinity increase combined with large enthalpy/entropy changes. However, first adding the carboxylate and then the methyl group yields reverse effects: the acidic group attachment now causes minor effects, whereas the added methyl group provokes large changes. As all crystal structures show virtually identical binding modes, affinity changes are related to rearrangements of the first solvation layer next to the S(2)' pocket. About 20-25 water molecules are visible next to the studied complexes. The added COO(-) groups perturb the local water network in both carboxylated complexes, and the attached methyl groups provide favorable interaction sites for water molecules. Apart from one example, a contiguously connected water network between protein and ligand functional groups is observed in all complexes. In the complex with the carboxylated ligand, which still lacks the terminal methyl group, the water network is unfavorably ruptured. This results in a surprising thermodynamic signature showing only a minor affinity increase upon COO(-) group attachment. Because the further added methyl group provides a favorable interaction site for water, the network can be reestablished, and a strong affinity increase with a large enthalpy/entropy signature is then detected.

PubMed: 22733601
DOI: 10.1002/cmdc.201200206

Experimental method

X-RAY DIFFRACTION (1.6 Å)