4MWP: Thermolysin In Complex With Ubtln46

Citation:
Abstract
Water is ubiquitously present in any biological system and has therefore to be regarded as an additional binding partner in the protein-ligand binding process. Upon complex formation, a new solvent-exposed surface is generated and water molecules from the first solvation layer will arrange around this newly formed surface. So far, the influence of such water arrangements on the ligand binding properties is unknown. In this study, the binding modes of nine congeneric phosphonamidate-type inhibitors with systematically varied, size-increasing hydrophobic P2 ' substituents (from methyl to phenylethyl) addressing the hydrophobic, solvent-exposed S2 ' pocket of thermolysin were analyzed by high-resolution crystal structures and correlated with their thermodynamic binding profiles as measured by isothermal titration calorimetry. Overall, DeltaDeltaG spreads over 7.0 kJ mol(-1) , DeltaDeltaH varies by 15.8 kJ mol(-1) , and -TDeltaDeltaS by 12.1 kJ mol(-1) . Throughout the series, these changes correlate remarkably well with the geometric differences of water molecules arranged adjacent to the P2 ' substituents. Ligands with medium-sized P2 ' substituents exhibit highest affinities, presumably because of their optimal solvation patterns around these complexes. The addition, removal, or rearrangement of even a single methyl group can result in a strong modulation of the adjacent water network pattern shifting from enthalpy to entropy-driven binding. In conclusion, the quality of a water network assembled around a protein-ligand complex influences the enthalpy/entropy signature and can even modulate affinity to a surprising extent.
PDB ID: 4MWPDownload
MMDB ID: 118832
PDB Deposition Date: 2013/9/25
Updated in MMDB: 2014/05
Experimental Method:
x-ray diffraction
Resolution: 1.23  Å
Source Organism:
Similar Structures:
Biological Unit for 4MWP: monomeric; determined by author and by software (PISA)
Molecular Components in 4MWP
Label Count Molecule
Protein (1 molecule)
1
Thermolysin
Molecule annotation
Chemicals (13 molecules)
1
1
2
4
3
4
4
3
5
1
* Click molecule labels to explore molecular sequence information.

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