3o0u

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{{STRUCTURE_3o0u| PDB=3o0u | SCENE= }}
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==Cathepsin K covalently bound to a cyano-pyrimidine inhibitor with improved selectivity over hERG==
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===Cathepsin K covalently bound to a cyano-pyrimidine inhibitor with improved selectivity over hERG===
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<StructureSection load='3o0u' size='340' side='right' caption='[[3o0u]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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{{ABSTRACT_PUBMED_20843687}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3o0u]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3O0U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3O0U FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O47:3-{2-[(E)-IMINOMETHYL]-6-PROPYLPYRIMIDIN-4-YL}-N,N-DIMETHYL-5-(TRIFLUOROMETHYL)BENZAMIDE'>O47</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTSK, CTSO, CTSO2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3o0u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o0u OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3o0u RCSB], [http://www.ebi.ac.uk/pdbsum/3o0u PDBsum]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN]] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:[http://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>
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== Function ==
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[[http://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.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (&gt;1000-fold), displayed a highly attractive overall profile.
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==Disease==
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Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: Improving selectivity over hERG.,Rankovic Z, Cai J, Kerr J, Fradera X, Robinson J, Mistry A, Finlay W, McGarry G, Andrews F, Caulfield W, Cumming I, Dempster M, Waller J, Arbuckle W, Anderson M, Martin I, Mitchell A, Long C, Baugh M, Westwood P, Kinghorn E, Jones P, Uitdehaag JC, van Zeeland M, Potin D, Saniere L, Fouquet A, Chevallier F, Deronzier H, Dorleans C, Nicolai E Bioorg Med Chem Lett. 2010 Aug 24. PMID:20843687<ref>PMID:20843687</ref>
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[[http://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN]] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:[http://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>
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://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.
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</div>
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==About this Structure==
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[[3o0u]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3O0U OCA].
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==See Also==
==See Also==
*[[Cathepsin|Cathepsin]]
*[[Cathepsin|Cathepsin]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:020843687</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Cathepsin K]]
[[Category: Cathepsin K]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Fradera, X.]]
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[[Category: Fradera, X]]
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[[Category: Uitdehaag, J C.M.]]
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[[Category: Uitdehaag, J C.M]]
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[[Category: Zeeland, M van.]]
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[[Category: Zeeland, M van]]
[[Category: Bone]]
[[Category: Bone]]
[[Category: Covalent 2-cyano-pyrimidine inhibitor]]
[[Category: Covalent 2-cyano-pyrimidine inhibitor]]

Revision as of 07:15, 19 December 2014

Cathepsin K covalently bound to a cyano-pyrimidine inhibitor with improved selectivity over hERG

3o0u, resolution 1.80Å

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