2h7j
From Proteopedia
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| - | [[Image:2h7j.jpg|left|200px]]<br /><applet load="2h7j" size="350" color="white" frame="true" align="right" spinBox="true" | ||
| - | caption="2h7j, resolution 1.50Å" /> | ||
| - | '''Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.'''<br /> | ||
| - | == | + | ==Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.== |
| - | The substrate activity screening method, a substrate-based fragment | + | <StructureSection load='2h7j' size='340' side='right'caption='[[2h7j]], [[Resolution|resolution]] 1.50Å' 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]] 1.5Å</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 >1000-fold selectivity over cathepsins B, L, and K. | ||
| - | + | 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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| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 2h7j" style="background-color:#fffaf0;"></div> | |
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| - | + | ==See Also== | |
| + | *[[Cathepsin 3D structures|Cathepsin 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Ellman JA]] | ||
| + | [[Category: Hornsby M]] | ||
| + | [[Category: Lesley S]] | ||
| + | [[Category: Patterson AW]] | ||
| + | [[Category: Spraggon G]] | ||
| + | [[Category: Wood WJ]] | ||
Current revision
Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.
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