2ozr

File:2ozr.gif

spinqualitylabelsall models 2ozr, resolution 2.300Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

MMP13 Catalytic Domain Complexed with 4-{[1-methyl-2,4-dioxo-6-(3-phenylprop-1-yn-1-yl)-1,4-dihydroquinazolin-3(2H)-yl]methyl}benzoic acid

OverviewOverview

Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-dependent protease that, catalyzes the cleavage of type II collagen, the main structural protein in, articular cartilage. Excess MMP13 activity causes cartilage degradation in, osteoarthritis, making this protease an attractive therapeutic target., However, clinically tested MMP inhibitors have been associated with a, painful, joint-stiffening musculoskeletal side effect that may be due to, their lack of selectivity. In our efforts to develop a disease-modifying, osteoarthritis drug, we have discovered MMP13 inhibitors that differ, greatly from previous MMP inhibitors: they do not bind to the catalytic, zinc ion, they are noncompetitive with respect to substrate binding, and, they show extreme selectivity for inhibiting MMP13. By structure-based, drug design, we generated an orally active MMP13 inhibitor that, effectively reduces cartilage damage in vivo and does not induce joint, fibroplasias in a rat model of musculoskeletal syndrome side effects., Thus, highly selective inhibition of MMP13 in patients may overcome the, major safety and efficacy challenges that have limited previously tested, non-selective MMP inhibitors. MMP13 inhibitors such as the ones described, here will help further define the role of this protease in arthritis and, other diseases and may soon lead to drugs that safely halt cartilage, damage in patients.

About this StructureAbout this Structure

2OZR is a Single protein structure of sequence from Homo sapiens with ZN, CA, GG1 and HAE as ligands. Full crystallographic information is available from OCA.

ReferenceReference

Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 (MMP13) that reduces cartilage damage in vivo without joint fibroplasia side effects., Johnson AR, Pavlovsky AG, Ortwine DF, Prior F, Man CF, Bornemeier DA, Banotai CA, Mueller WT, McConnell P, Yan C, Baragi V, Lesch C, Roark WH, Wilson M, Datta K, Guzman R, Han HK, Dyer RD, J Biol Chem. 2007 Jul 10;. PMID:17623656

Page seeded by OCA on Mon Nov 12 23:18:41 2007