2ato
From Proteopedia
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caption="2ato, resolution 2.00Å" /> | caption="2ato, resolution 2.00Å" /> | ||
'''Crystal structure of Human Cathepsin K in complex with myocrisin'''<br /> | '''Crystal structure of Human Cathepsin K in complex with myocrisin'''<br /> | ||
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| + | ==Overview== | ||
| + | Rheumatoid arthritis is an inflammatory and disabling joint disease affecting 0.5-1.5% of the population. Although various anti-inflammatory (NSAIDs) and disease-modifying (DMARDs) drugs are in clinical use, their precise mechanisms of action are not always defined. In this report, we discuss the effects of widely used DMARDs such as gold derivatives and chloroquine on cathepsins K and S, which have been implicated as critical mediators of inflammation and joint erosion in rheumatoid arthritis. We demonstrate that clinically potent gold derivatives inhibit cathepsins K and S in in vitro and cell-based assays. An X-ray analysis of the gold thiomalate/cathepsin K complex reveals that the inhibitor is bound to the active-site cysteine residue of the protease. Chloroquine, a lysosomotropic agent of lower clinical potency than gold derivatives, inhibits neutral pH-labile cathepsins intracellularly, but does not affect the neutral pH-stable cathepsin S. The potent inhibition of cathepsins implicated in the pathogenesis of rheumatoid arthritis by gold derivatives may explain the therapeutic efficacy of these drugs. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2ATO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=MYQ:'>MYQ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Cathepsin_K Cathepsin K], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.38 3.4.22.38] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ATO OCA]. | 2ATO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=MYQ:'>MYQ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Cathepsin_K Cathepsin K], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.38 3.4.22.38] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ATO OCA]. | ||
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| + | ==Reference== | ||
| + | Effects of disease-modifying anti-rheumatic drugs (DMARDs) on the activities of rheumatoid arthritis-associated cathepsins K and S., Weidauer E, Yasuda Y, Biswal BK, Cherny M, James MN, Bromme D, Biol Chem. 2007 Mar;388(3):331-6. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17338641 17338641] | ||
[[Category: Cathepsin K]] | [[Category: Cathepsin K]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Biswal, B | + | [[Category: Biswal, B K.]] |
[[Category: Bromme, D.]] | [[Category: Bromme, D.]] | ||
| - | [[Category: Cherney, M | + | [[Category: Cherney, M M.]] |
| - | [[Category: Gordon, R | + | [[Category: Gordon, R E.]] |
| - | [[Category: James, M | + | [[Category: James, M N.G.]] |
| - | [[Category: Kerr, L | + | [[Category: Kerr, L D.]] |
[[Category: Weidauer, E.]] | [[Category: Weidauer, E.]] | ||
[[Category: Yasuda, Y.]] | [[Category: Yasuda, Y.]] | ||
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[[Category: myocrysin]] | [[Category: myocrysin]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:30:54 2008'' |
Revision as of 14:30, 21 February 2008
|
Crystal structure of Human Cathepsin K in complex with myocrisin
Contents |
Overview
Rheumatoid arthritis is an inflammatory and disabling joint disease affecting 0.5-1.5% of the population. Although various anti-inflammatory (NSAIDs) and disease-modifying (DMARDs) drugs are in clinical use, their precise mechanisms of action are not always defined. In this report, we discuss the effects of widely used DMARDs such as gold derivatives and chloroquine on cathepsins K and S, which have been implicated as critical mediators of inflammation and joint erosion in rheumatoid arthritis. We demonstrate that clinically potent gold derivatives inhibit cathepsins K and S in in vitro and cell-based assays. An X-ray analysis of the gold thiomalate/cathepsin K complex reveals that the inhibitor is bound to the active-site cysteine residue of the protease. Chloroquine, a lysosomotropic agent of lower clinical potency than gold derivatives, inhibits neutral pH-labile cathepsins intracellularly, but does not affect the neutral pH-stable cathepsin S. The potent inhibition of cathepsins implicated in the pathogenesis of rheumatoid arthritis by gold derivatives may explain the therapeutic efficacy of these drugs.
Disease
Known disease associated with this structure: Pycnodysostosis OMIM:[601105]
About this Structure
2ATO is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Cathepsin K, with EC number 3.4.22.38 Full crystallographic information is available from OCA.
Reference
Effects of disease-modifying anti-rheumatic drugs (DMARDs) on the activities of rheumatoid arthritis-associated cathepsins K and S., Weidauer E, Yasuda Y, Biswal BK, Cherny M, James MN, Bromme D, Biol Chem. 2007 Mar;388(3):331-6. PMID:17338641
Page seeded by OCA on Thu Feb 21 16:30:54 2008
Categories: Cathepsin K | Homo sapiens | Single protein | Biswal, B K. | Bromme, D. | Cherney, M M. | Gordon, R E. | James, M N.G. | Kerr, L D. | Weidauer, E. | Yasuda, Y. | MYQ | SO4 | Cathepsin k | Myocrysin
