PDBsum entry 3tvc

Hydrolase/hydrolase inhibitor

PDB id: 3tvc

Contents

Protein chain

169 a.a.

Ligands

E3P

PEG ×3

Metals

_ZN ×2

_CA ×3

Waters ×105

PDB id:

3tvc

Name:

Hydrolase/hydrolase inhibitor

Title:

Human mmp13 in complex with l-glutamate motif inhibitor

Structure:

Collagenase 3. Chain: a. Fragment: mmp-13 catalytic subunit (unp residues 104-272). Synonym: matrix metalloproteinase-13, mmp-13. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mmp13. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.43Å R-factor: 0.165 R-free: 0.234

Authors:

E.A.Stura,V.Dive,L.Devel,B.Czarny,F.Beau,L.Vera,E.Cassar-Lajeunesse

Key ref:

L.Devel et al. (2012). Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins. J Biol Chem, 287, 26647-26656. PubMed id: 22689580

Date:

20-Sep-11 Release date: 20-Jun-12

Protein chain

P45452  (MMP13_HUMAN) -  Collagenase 3 from Homo sapiens

Seq: 471 a.a.

Struc: 169 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.24.- - ?????

J Biol Chem 287:26647-26656 (2012)

PubMed id: 22689580

Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins.

L.Devel, F.Beau, M.Amoura, L.Vera, E.Cassar-Lajeunesse, S.Garcia, B.Czarny, E.A.Stura, V.Dive.

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.