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2h7j

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[[Image:2h7j.jpg|left|200px]]<br /><applet load="2h7j" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2h7j, resolution 1.50&Aring;" />
 
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'''Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.'''<br />
 
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==Overview==
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==Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.==
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The substrate activity screening method, a substrate-based fragment, identification and optimization method for the development of enzyme, inhibitors, was previously applied to cathepsin S to obtain low nanomolar, 1,4-disubstituted-1,2,3-triazole-based aldehyde inhibitors (Wood, W. J., L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am., Chem. Soc. 2005, 127, 15521-15527). Replacement of the metabolically, labile aldehyde pharmacophore with the nitrile pharmacophore provided, inhibitors with moderate potency for cathepsin S. The inhibitors showed, good selectivity over cathepsins B and L but no selectivity over cathepsin, K. X-ray structures of two crystal forms (1.5 and 1.9 A) of a complex, between cathepsin S and a triazole inhibitor incorporating a chloromethyl, ketone pharmacophore guided the design of triazole substrates with, increased cleavage efficiency and selectivity for cathepsin S over, cathepsins B, L, and K. Conversion of select substrates to nitrile, inhibitors yielded a low molecular weight (414 Da) and potent (15 nM), cathepsin S inhibitor that showed &gt;1000-fold selectivity over cathepsins, B, L, and K.
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<StructureSection load='2h7j' size='340' side='right'caption='[[2h7j]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2h7j]] is a 2 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=2H7J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2H7J FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H7J:N-[(1S)-1-{1-[(1R,3E)-1-ACETYLPENT-3-EN-1-YL]-1H-1,2,3-TRIAZOL-4-YL}-1,2-DIMETHYLPROPYL]BENZAMIDE'>H7J</scene>, <scene name='pdbligand=P15:2,5,8,11,14,17-HEXAOXANONADECAN-19-OL'>P15</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2h7j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h7j OCA], [https://pdbe.org/2h7j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2h7j RCSB], [https://www.ebi.ac.uk/pdbsum/2h7j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2h7j ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/CATS_HUMAN CATS_HUMAN] Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules. The bond-specificity of this proteinase is in part similar to the specificities of cathepsin L and cathepsin N.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h7/2h7j_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2h7j ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The substrate activity screening method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain low nanomolar 1,4-disubstituted-1,2,3-triazole-based aldehyde inhibitors (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). Replacement of the metabolically labile aldehyde pharmacophore with the nitrile pharmacophore provided inhibitors with moderate potency for cathepsin S. The inhibitors showed good selectivity over cathepsins B and L but no selectivity over cathepsin K. X-ray structures of two crystal forms (1.5 and 1.9 A) of a complex between cathepsin S and a triazole inhibitor incorporating a chloromethyl ketone pharmacophore guided the design of triazole substrates with increased cleavage efficiency and selectivity for cathepsin S over cathepsins B, L, and K. Conversion of select substrates to nitrile inhibitors yielded a low molecular weight (414 Da) and potent (15 nM) cathepsin S inhibitor that showed &gt;1000-fold selectivity over cathepsins B, L, and K.
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==About this Structure==
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Identification of selective, nonpeptidic nitrile inhibitors of cathepsin s using the substrate activity screening method.,Patterson AW, Wood WJ, Hornsby M, Lesley S, Spraggon G, Ellman JA J Med Chem. 2006 Oct 19;49(21):6298-307. PMID:17034136<ref>PMID:17034136</ref>
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2H7J 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=H7J:'>H7J</scene> and <scene name='pdbligand=P15:'>P15</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Cathepsin_S Cathepsin S], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.27 3.4.22.27] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7J OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Identification of selective, nonpeptidic nitrile inhibitors of cathepsin s using the substrate activity screening method., Patterson AW, Wood WJ, Hornsby M, Lesley S, Spraggon G, Ellman JA, J Med Chem. 2006 Oct 19;49(21):6298-307. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17034136 17034136]
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</div>
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[[Category: Cathepsin S]]
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<div class="pdbe-citations 2h7j" style="background-color:#fffaf0;"></div>
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[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Ellman, J.A.]]
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[[Category: Hornsby, M.]]
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[[Category: Lesley, S.]]
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[[Category: Patterson, A.W.]]
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[[Category: Spraggon, G.]]
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[[Category: Wood, W.J.]]
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[[Category: H7J]]
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[[Category: P15]]
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[[Category: cathepsin s]]
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[[Category: chloromethylketone]]
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[[Category: nonpeptidic]]
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[[Category: substrate activity screening]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:30:20 2008''
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==See Also==
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*[[Cathepsin 3D structures|Cathepsin 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Ellman JA]]
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[[Category: Hornsby M]]
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[[Category: Lesley S]]
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[[Category: Patterson AW]]
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[[Category: Spraggon G]]
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[[Category: Wood WJ]]

Current revision

Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.

PDB ID 2h7j

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