4GQL

Crystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470.1

Summary for 4GQL

• Entry DOI: 10.2210/pdb4gql/pdb
• Related: 3LIK 3LIL 3LIR 3LJG 3TS4 3TSK 4EFS 4GR0 4GR3 4GR8
• Related PRD ID: PRD_000830
• Descriptor: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: potent selective phosphinic inhibitor, metzincin, zinc protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix (Probable): P39900
• Total number of polymer chains: 1
• Total formula weight: 18684.73

Authors

Stura, E.A.,Vera, L.,Beau, F.,Devel, L.,Cassar-Lajeunesse, E.,Dive, V. (deposition date: 2012-08-23, release date: 2013-02-06, Last modification date: 2023-09-13)

Primary citation

Czarny, B.,Stura, E.A.,Devel, L.,Vera, L.,Cassar-Lajeunesse, E.,Beau, F.,Calderone, V.,Fragai, M.,Luchinat, C.,Dive, V.
Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies.
J.Med.Chem., 56:1149-1159, 2013

PubMed Abstract: 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.

PubMed: 23343195
DOI: 10.1021/jm301574d

Experimental method

X-RAY DIFFRACTION (1.15 Å)