2ozr

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[[Image:2ozr.gif|left|200px]]
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{{Seed}}
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{{STRUCTURE_2ozr| PDB=2ozr | SCENE= }}
{{STRUCTURE_2ozr| PDB=2ozr | SCENE= }}
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'''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'''
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===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===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 17623656 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17623656}}
==About this Structure==
==About this Structure==
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[[Category: Mmp13 catalytic domain]]
[[Category: Mmp13 catalytic domain]]
[[Category: Mmp13 specific inhibitor]]
[[Category: Mmp13 specific inhibitor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 12:00:52 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 13:40:44 2008''

Revision as of 10:40, 28 July 2008

Image:2ozr.png

Template:STRUCTURE 2ozr

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

Template:ABSTRACT PUBMED 17623656

About this Structure

2OZR is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 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 Sep 21;282(38):27781-91. Epub 2007 Jul 10. PMID:17623656

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