2ozr

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[[Image:2ozr.gif|left|200px]]
[[Image:2ozr.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 2ozr |SIZE=350|CAPTION= <scene name='initialview01'>2ozr</scene>, resolution 2.300&Aring;
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The line below this paragraph, containing "STRUCTURE_2ozr", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GG1:4-{[1-METHYL-2,4-DIOXO-6-(3-PHENYLPROP-1-YN-1-YL)-1,4-DIHYDROQUINAZOLIN-3(2H)-YL]METHYL}BENZOIC+ACID'>GG1</scene>, <scene name='pdbligand=HAE:ACETOHYDROXAMIC+ACID'>HAE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY=
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or leave the SCENE parameter empty for the default display.
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|GENE= MMP13 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_2ozr| PDB=2ozr | SCENE= }}
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|RELATEDENTRY=[[2ow9|2OW9]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ozr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ozr OCA], [http://www.ebi.ac.uk/pdbsum/2ozr PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ozr RCSB]</span>
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}}
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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'''
'''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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[[Category: Wilson, M.]]
[[Category: Wilson, M.]]
[[Category: Yan, C H.]]
[[Category: Yan, C H.]]
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[[Category: crystal complex structure]]
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[[Category: Crystal complex structure]]
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[[Category: hydrolase]]
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[[Category: Hydrolase]]
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[[Category: matrix metalloproteinase]]
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[[Category: Matrix metalloproteinase]]
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[[Category: mmp13 catalytic domain]]
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[[Category: Mmp13 catalytic domain]]
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[[Category: mmp13 specific inhibitor]]
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[[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 Mar 31 04:25:38 2008''
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Revision as of 09:00, 4 May 2008

Image:2ozr.gif

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


Overview

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 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 Page seeded by OCA on Sun May 4 12:00:52 2008

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OCA

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