PDB 3TS4 deposited: 2011-09-12 modified: 2012-10-17
Title Human MMP12 in complex with L-glutamate motif inhibitor
Authors Amoura, M., Beau, F., Cassar-Lajeunesse, E., Czarny, B., Devel, L., Dive, V., Garcia, S., Stura, E.A., Vera, L.
Structure factors resolution 1.587 rfactor 0.1784 rfree 0.203
DPI 0.22 theoretical min: 0.09
Related PDB Entries 3TSK 3TT4 3TVC 4EFS

A series of pseudo-peptides with general formula X-l-Glu-NH(2) (with X corresponding to an acyl moiety with a long aryl-alkyl side chain) have been synthesized, evaluated as inhibitors of matrix metalloproteases (MMPs), and found to display remarkable nanomolar affinity. The loss in potency associated with a substitution of the P(2)' l-glutamate by a l-glutamine corroborates the importance of a carboxylate at this position. The binding mode of some of these inhibitors was characterized in solution and by x-ray crystallography in complex with various MMPs. The x-ray crystal structures reveal an unusual binding mode with the glutamate side chain chelating the active site zinc ion. Competition experiments between these inhibitors and acetohydroxamic acid, a small zinc-binding molecule, are in accord with the crystallographic results. One of these pseudo-dipeptides displays potency and selectivity toward MMP-12 similar to the best MMP-12 inhibitors reported to date. This novel family of pseudo peptides opens new opportunities to develop potent and selective inhibitors for several metzincins.

J.Biol.Chem. 2012 Aug; 287(32):26647-26656 doi:10.1074/jbc.M112.380782

Cross References
Database source Identifier Description
PubMed 22689580 JBCHA3
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3TS4/0 3TS4 0 monomer 0 1 8 1463