2ato: Difference between revisions
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==Crystal structure of Human Cathepsin K in complex with myocrisin== | |||
<StructureSection load='2ato' size='340' side='right'caption='[[2ato]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2ato]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ATO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ATO FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MYQ:(S)-(1,2-DICARBOXYETHYLTHIO)GOLD'>MYQ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ato FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ato OCA], [https://pdbe.org/2ato PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ato RCSB], [https://www.ebi.ac.uk/pdbsum/2ato PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ato ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:[https://omim.org/entry/265800 265800]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.<ref>PMID:8703060</ref> <ref>PMID:9529353</ref> <ref>PMID:10491211</ref> <ref>PMID:10878663</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/at/2ato_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ato ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:17338641</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2ato" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Cathepsin|Cathepsin]] | *[[Cathepsin 3D structures|Cathepsin 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Biswal | [[Category: Large Structures]] | ||
[[Category: Bromme | [[Category: Biswal BK]] | ||
[[Category: Cherney | [[Category: Bromme D]] | ||
[[Category: Gordon | [[Category: Cherney MM]] | ||
[[Category: James | [[Category: Gordon RE]] | ||
[[Category: Kerr | [[Category: James MNG]] | ||
[[Category: Weidauer | [[Category: Kerr LD]] | ||
[[Category: Yasuda | [[Category: Weidauer E]] | ||
[[Category: Yasuda Y]] | |||
Latest revision as of 10:50, 30 October 2024
Crystal structure of Human Cathepsin K in complex with myocrisinCrystal structure of Human Cathepsin K in complex with myocrisin
Structural highlights
DiseaseCATK_HUMAN Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:265800. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.[1] [2] [3] [4] FunctionCATK_HUMAN Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedRheumatoid 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. 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[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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