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PDBsum entry 3tvc
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Hydrolase/hydrolase inhibitor
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PDB id
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3tvc
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References listed in PDB file
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Key reference
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Title
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Simple pseudo-Dipeptides with a p2' Glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins.
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Authors
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L.Devel,
F.Beau,
M.Amoura,
L.Vera,
E.Cassar-Lajeunesse,
S.Garcia,
B.Czarny,
E.A.Stura,
V.Dive.
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Ref.
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J Biol Chem, 2012,
287,
26647-26656.
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PubMed id
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Abstract
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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.
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