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PDBsum entry 3t73

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protein ligands metals links
Hydrolase/hydrolase inhibitor PDB id
3t73
Jmol
Contents
Protein chain
316 a.a.
Ligands
UBX
GOL ×4
DMS ×4
Metals
_CA ×4
_ZN
Waters ×400
PDB id:
3t73
Name: Hydrolase/hydrolase inhibitor
Title: Thermolysin in complex with ubtln22
Structure: Thermolysin. Chain: a. Fragment: mature form (unp residues 233-548). Synonym: thermostable neutral proteinase. Ec: 3.4.24.27
Source: Bacillus thermoproteolyticus. Organism_taxid: 1427
Resolution:
1.60Å     R-factor:   0.144     R-free:   0.166
Authors: A.Biela,A.Heine,G.Klebe
Key ref: A.Biela et al. (2012). Water makes the difference: rearrangement of water solvation layer triggers non-additivity of functional group contributions in protein-ligand binding. ChemMedChem, 7, 1423-1434. PubMed id: 22733601
Date:
29-Jul-11     Release date:   01-Aug-12    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00800  (THER_BACTH) -  Thermolysin
Seq:
Struc:
 
Seq:
Struc:
548 a.a.
316 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.24.27  - Thermolysin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Xaa-|-Leu > Xaa-|-Phe.
      Cofactor: Ca(2+); Zn(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     metalloendopeptidase activity     1 term  

 

 
ChemMedChem 7:1423-1434 (2012)
PubMed id: 22733601  
 
 
Water makes the difference: rearrangement of water solvation layer triggers non-additivity of functional group contributions in protein-ligand binding.
A.Biela, M.Betz, A.Heine, G.Klebe.
 
  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.