PDB 4GQL deposited: 2012-08-23 modified: 2013-05-22
Title Crystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470.1
Authors Beau, F., Calderone, V., Cassar-Lajeunesse, E., Czarny, B., Devel, L., Dive, V., Fragai, M., Luchinat, C., Stura, E.A., Vera, L.
Structure factors resolution 1.15 rfactor 0.1333 rfree 0.1545
DPI 0.08 theoretical min: 0.03
Related PDB Entries 4GR0 4GR3 4GR8

The molecular determinants responsible for the potency of the RXP470.1 phosphinic peptide inhibitor toward matrix metalloprotease-12 (MMP-12) remain elusive. To address this issue, structure-activity study, X-ray crystallography, and isothermal titration calorimetry (ITC) experiments were performed. The crystal structure of MMP-12/inhibitor complex (1.15 Å) reveals that the inhibitor establishes multiple interactions with the MMP-12 active site, with its long P(1)' side chain filling most of the S(1)' deep cavity. ITC experiments indicate that the binding of this inhibitor to MMP-12 is mostly entropy driven (ΔG° = -13.1 kcal/mol, ΔH° = -2.53 kcal/mol, and -TΔS° = -10.60 kcal/mol) and involves a proton uptake from the buffer. Comparing phosphinic versus hydroxamate inhibitors reveals that the chelation of the zinc ion is slightly different, leading the inhibitor backbone to adopt a position in which the hydrogen bonding with the MMP-12 active site is less favorable in phosphinic inhibitor while maintaining high affinity.

J.Med.Chem. 2013 Feb; 56(3):1149-1159 doi:10.1021/jm301574d

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL2311401
PubMed 23343195 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4GQL/0 4GQL 0 monomer 0 1 6 1578