PDBsum entry: 1d5j

Hydrolase

PDB id: 1d5j

Contents

Protein chains

169 a.a. *

Ligands

MM3 ×2

Metals

_ZN ×4

_CA ×6

Waters ×89

* Residue conservation analysis

PDB id:

1d5j

Name:

Hydrolase

Title:

Crystal structure of mmp3 complexed with a thiazepine based inhibitor.

Structure:

Stromelysin-1. Chain: a, b. Fragment: catalytic domain. Synonym: mmp-3. Engineered: yes

Source:

Synthetic: yes. Other_details: the polymer was organically synthesized in escherichia coli from the fibroblast cell of homo sapiens (humans)

Resolution:

2.60Å R-factor: 0.237 R-free: 0.257

Authors:

N.G.Almstead,R.S.Bradley,S.Pikul,B.De,M.G.Natchus

Key ref:

N.G.Almstead et al. (1999). Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors. J Med Chem, 42, 4547-4562. PubMed id: 10579818 DOI: 10.1021/jm990330y

Date:

07-Oct-99 Release date: 09-Oct-00

Protein chains

P08254  (MMP3_HUMAN) -  Stromelysin-1

Seq: 477 a.a.

Struc: 169 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)

DOI no: 10.1021/jm990330y

J Med Chem 42:4547-4562 (1999)

PubMed id: 10579818

Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors.

N.G.Almstead, R.S.Bradley, S.Pikul, B.De, M.G.Natchus, Y.O.Taiwo, F.Gu, L.E.Williams, B.A.Hynd, M.J.Janusz, C.M.Dunaway, G.E.Mieling.

ABSTRACT

The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.