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New page: left|200px<br /> <applet load="2h7j" size="450" color="white" frame="true" align="right" spinBox="true" caption="2h7j, resolution 1.50Å" /> '''Crystal Structure o...
 
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[[Image:2h7j.gif|left|200px]]<br />
<applet load="2h7j" size="450" color="white" frame="true" align="right" spinBox="true"
caption="2h7j, resolution 1.50&Aring;" />
'''Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.'''<br />


==Overview==
==Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.==
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.
<StructureSection load='2h7j' size='340' side='right'caption='[[2h7j]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<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>
</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>
<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>
<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>
</table>
== Function ==
[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.
== 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/h7/2h7j_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=2h7j ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


==About this Structure==
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>
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 H7J and P15 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2H7J OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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]
</div>
[[Category: Cathepsin S]]
<div class="pdbe-citations 2h7j" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Cathepsin 3D structures|Cathepsin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Ellman, J.A.]]
[[Category: Ellman JA]]
[[Category: Hornsby, M.]]
[[Category: Hornsby M]]
[[Category: Lesley, S.]]
[[Category: Lesley S]]
[[Category: Patterson, A.W.]]
[[Category: Patterson AW]]
[[Category: Spraggon, G.]]
[[Category: Spraggon G]]
[[Category: Wood, W.J.]]
[[Category: Wood WJ]]
[[Category: H7J]]
[[Category: P15]]
[[Category: cathepsin s]]
[[Category: chloromethylketone]]
[[Category: nonpeptidic]]
[[Category: substrate activity screening]]
 
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