PDBsum entry 4n4e

Hydrolase/hydrolase inhibitor

PDB id: 4n4e

Contents

Protein chain

316 a.a.

Ligands

DMS ×3

GOL ×3

2G6

Metals

_ZN

_CA ×4

Waters ×462

PDB id:

4n4e

Name:

Hydrolase/hydrolase inhibitor

Title:

Thermolysin in complex with ubtln58

Structure:

Thermolysin. Chain: e. Fragment: mature form (unp residues 233-548). Synonym: thermostable neutral proteinase. Ec: 3.4.24.27

Source:

Bacillus thermoproteolyticus. Organism_taxid: 1427

Resolution:

1.13Å R-factor: 0.122 R-free: 0.138

Authors:

S.G.Krimmer,A.Heine,G.Klebe

Key ref:

S.G.Krimmer et al. (2014). Methyl, ethyl, propyl, butyl: futile but not for water, as the correlation of structure and thermodynamic signature shows in a congeneric series of thermolysin inhibitors. Chemmedchem, 9, 833-846. PubMed id: 24623396 DOI: 10.1002/cmdc.201400013

Date:

08-Oct-13 Release date: 02-Apr-14

Protein chain

P00800  (THER_BACTH) -  Thermolysin from Bacillus thermoproteolyticus

Seq: 548 a.a.

Struc: 316 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.24.27 - thermolysin.
• Reaction: Preferential cleavage: Xaa-|-Leu > Xaa-|-Phe.
• Cofactor: Ca(2+); Zn(2+)

DOI no: 10.1002/cmdc.201400013

Chemmedchem 9:833-846 (2014)

PubMed id: 24623396

Methyl, ethyl, propyl, butyl: futile but not for water, as the correlation of structure and thermodynamic signature shows in a congeneric series of thermolysin inhibitors.

S.G.Krimmer, M.Betz, A.Heine, G.Klebe.

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, ΔΔG spreads over 7.0 kJ mol(-1) , ΔΔH varies by 15.8 kJ mol(-1) , and -TΔΔS 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.