PDBsum entry: 1ciz

Metalloproteinase

PDB id: 1ciz

Contents

Protein chain

168 a.a. *

Ligands

SO4

DPS

Metals

_ZN ×2

_CA ×3

Waters ×147

* Residue conservation analysis

PDB id:

1ciz

Name:

Metalloproteinase

Title:

X-ray structure of human stromelysin catalytic domain comple non-peptide inhibitors: implication for inhibitor selectivi

Structure:

Protein (stromelysin-1). Chain: a. Fragment: catalytic domain. Synonym: matrix metalloproteinase-3. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: fibroblast. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

1.64Å R-factor: 0.209 R-free: 0.245

Authors:

A.G.Pavlovsky,M.G.Williams,Q.-Z.Ye,D.F.Ortwine,C.F.Purchase A.D.White,V.Dhanaraj,B.D.Roth,L.L.Johnson,D.Hupe,C.Humblet, T.L.Blundell

Key ref:

A.G.Pavlovsky et al. (1999). X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity. Protein Sci, 8, 1455-1462. PubMed id: 10422833 Ref: Full text

Date:

06-Apr-99 Release date: 01-Sep-99

Protein chain

P08254  (MMP3_HUMAN) -  Stromelysin-1

Seq: 477 a.a.

Struc: 168 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.24.17 - Stromelysin 1.
• Reaction: Preferential cleavage where P1', P2' and P3' are hydrophobic residues.
• Cofactor: Calcium; Zinc

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular matrix (1 term)
• Biological process: proteolysis (1 term)
• Biochemical function: metallopeptidase activity (3 terms)

Full text	Protein Sci 8:1455-1462 (1999)
PubMed id: 10422833

X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity.

A.G.Pavlovsky, M.G.Williams, Q.Z.Ye, D.F.Ortwine, C.F.Purchase, A.D.White, V.Dhanaraj, B.D.Roth, L.L.Johnson, D.Hupe, C.Humblet, T.L.Blundell.

ABSTRACT

Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 A. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S'1 pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S'1 pocket. The largest differences occur in the loop forming the "top" of this pocket. The occupation of these nonpeptidic inhibitors in the S'1 pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.