3TT4: Human Mmp8 In Complex With L-Glutamate Motif Inhibitor

Citation:
Abstract
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.
PDB ID: 3TT4Download
MMDB ID: 100665
PDB Deposition Date: 2011/9/14
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 1.88  Å
Source Organism:
Similar Structures:
Biological Unit for 3TT4: monomeric; determined by author and by software (PISA)
Molecular Components in 3TT4
Label Count Molecule
Protein (1 molecule)
1
Neutrophil Collagenase(Gene symbol: MMP8)
Molecule annotation
Chemicals (6 molecules)
1
2
2
2
3
1
4
1
* Click molecule labels to explore molecular sequence information.

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