5D3C

Crystal structure of a double mutant catalytic domain of Human MMP12 in complex with an hydroxamate analogue of RXP470

Summary for 5D3C

• Entry DOI: 10.2210/pdb5d3c/pdb
• Descriptor: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: mmp12, human, macrophage metalloelastase, rxp470, hydroxamate, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P39900
• Total number of polymer chains: 1
• Total formula weight: 18466.68

Authors

Rouanet-Mehouas, C.,Devel, L.,Dive, V.,Stura, E.A. (deposition date: 2015-08-06, release date: 2016-08-17, Last modification date: 2024-01-10)

Primary citation

Rouanet-Mehouas, C.,Czarny, B.,Beau, F.,Cassar-Lajeunesse, E.,Stura, E.A.,Dive, V.,Devel, L.
Zinc-Metalloproteinase Inhibitors: Evaluation of the Complex Role Played by the Zinc-Binding Group on Potency and Selectivity.
J. Med. Chem., 60:403-414, 2017

PubMed Abstract: The most exploited strategy to develop potent zinc-metalloprotease inhibitors relies on a core zinc chelator and a peptidic or nonpeptidic scaffold that provides supplementary interactions for optimized potency and selectivity. Applied to matrix metalloproteases (MMPs) with highly conserved catalytic domains, this strategy failed to identify inhibitors with the desired selectivity profiles. To question the precise role of the zinc-binding group (ZBG), we have carried out a study on MMP-12 inhibitors with a common peptidic core but different ZBGs. We find that exchanging the ZBG modifies inhibitor positioning and affects its dynamics and selectivity. The binding properties of these compounds were compared through biochemical, structural, and calorimetric studies, showing a complex interplay between cooperative interactions and dynamics dictated by the ZBG. Improving selectivity will require expanding the ZBG repertoire within inhibitor libraries, since relying on a single ZBG significantly decreases our chance to identify effective inhibitors.

PubMed: 27996256
DOI: 10.1021/acs.jmedchem.6b01420

Experimental method

X-RAY DIFFRACTION (1.314 Å)