5CXA: Crystal Structure Of The Catalytic Domain Of Human Mmp12 In Complex With A Carboxylate Inhibitor Related To Rxp470

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.
PDB ID: 5CXADownload
MMDB ID: 142045
PDB Deposition Date: 2015/7/28
Updated in MMDB: 2016/12
Experimental Method:
x-ray diffraction
Resolution: 1.3  Å
Source Organism:
Similar Structures:
Biological Unit for 5CXA: monomeric; determined by author and by software (PISA)
Molecular Components in 5CXA
Label Count Molecule
Protein (1 molecule)
Macrophage Metalloelastase(Gene symbol: MMP12)
Molecule annotation
Chemicals (6 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB