2ow9
From Proteopedia
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|PDB= 2ow9 |SIZE=350|CAPTION= <scene name='initialview01'>2ow9</scene>, resolution 1.740Å | |PDB= 2ow9 |SIZE=350|CAPTION= <scene name='initialview01'>2ow9</scene>, resolution 1.740Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand= | + | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=HAE:ACETOHYDROXAMIC+ACID'>HAE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SP6:BENZYL+6-BENZYL-5,7-DIOXO-6,7-DIHYDRO-5H-[1,3]THIAZOLO[3,2-C]PYRIMIDINE-2-CARBOXYLATE'>SP6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= MMP13 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= MMP13 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ow9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ow9 OCA], [http://www.ebi.ac.uk/pdbsum/2ow9 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ow9 RCSB]</span> | ||
}} | }} | ||
| Line 23: | Line 26: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Pavlovsky, A G.]] | [[Category: Pavlovsky, A G.]] | ||
| - | [[Category: CA]] | ||
| - | [[Category: HAE]] | ||
| - | [[Category: SO4]] | ||
| - | [[Category: SP6]] | ||
| - | [[Category: ZN]] | ||
[[Category: complex crystal structure]] | [[Category: complex crystal structure]] | ||
[[Category: hydrolase]] | [[Category: hydrolase]] | ||
| Line 35: | Line 33: | ||
[[Category: specific mmp13 inhibitor]] | [[Category: specific mmp13 inhibitor]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:24:06 2008'' |
Revision as of 01:24, 31 March 2008
| |||||||
| , resolution 1.740Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , , | ||||||
| Gene: | MMP13 (Homo sapiens) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure analysis of the MMP13 catalytic domain in complex with specific inhibitor
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
2OW9 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 Mon Mar 31 04:24:06 2008
