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[[Image:2op3.jpg|left|200px]]


{{Structure
==The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method==
|PDB= 2op3 |SIZE=350|CAPTION= <scene name='initialview01'>2op3</scene>, resolution 1.60&Aring;
<StructureSection load='2op3' size='340' side='right'caption='[[2op3]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=PEU:2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80-HEPTACOSAOXADOOCTACONTAN-82-OL'>PEU</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TF5:2-[(2&#39;,3&#39;,4&#39;-TRIFLUOROBIPHENYL-2-YL)OXY]ETHANOL'>TF5</scene>
<table><tr><td colspan='2'>[[2op3]] 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=2OP3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OP3 FirstGlance]. <br>
|ACTIVITY= <span class='plainlinks'>[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] </span>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
|GENE= CATHS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PEU:2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80-HEPTACOSAOXADOOCTACONTAN-82-OL'>PEU</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TF5:2-[(2,3,4-TRIFLUOROBIPHENYL-2-YL)OXY]ETHANOL'>TF5</scene></td></tr>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2op3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2op3 OCA], [https://pdbe.org/2op3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2op3 RCSB], [https://www.ebi.ac.uk/pdbsum/2op3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2op3 ProSAT]</span></td></tr>
|RELATEDENTRY=[[2hxz|2HXZ]], [[2h7j|2H7J]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2op3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2op3 OCA], [http://www.ebi.ac.uk/pdbsum/2op3 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2op3 RCSB]</span>
== 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/op/2op3_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=2op3 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The substrate activity screening (SAS) method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain a novel (2-arylphenoxy)acetaldehyde inhibitor, 2, with a 0.49 microM Ki value (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). In this paper we disclose the X-ray structure of a complex between cathepsin S and inhibitor 2 which reveals an unprecedented binding mode. On the basis of this structure, additional 2-biaryloxy substrates with greatly increased cleavage efficiency were designed. Conversion of the optimized substrates to the corresponding aldehyde inhibitors yielded a low molecular weight (304 Daltons) and potent (9.6 nM) cathepsin S inhibitor that showed from 100- to &gt;1000-fold selectivity relative to cathepsins B, L, and K.


'''The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method'''
Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode.,Inagaki H, Tsuruoka H, Hornsby M, Lesley SA, Spraggon G, Ellman JA J Med Chem. 2007 May 31;50(11):2693-9. Epub 2007 May 1. PMID:17469812<ref>PMID:17469812</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2op3" style="background-color:#fffaf0;"></div>


==Overview==
==See Also==
The substrate activity screening (SAS) method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain a novel (2-arylphenoxy)acetaldehyde inhibitor, 2, with a 0.49 microM Ki value (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). In this paper we disclose the X-ray structure of a complex between cathepsin S and inhibitor 2 which reveals an unprecedented binding mode. On the basis of this structure, additional 2-biaryloxy substrates with greatly increased cleavage efficiency were designed. Conversion of the optimized substrates to the corresponding aldehyde inhibitors yielded a low molecular weight (304 Daltons) and potent (9.6 nM) cathepsin S inhibitor that showed from 100- to &gt;1000-fold selectivity relative to cathepsins B, L, and K.
*[[Cathepsin 3D structures|Cathepsin 3D structures]]
 
== References ==
==About this Structure==
<references/>
2OP3 is a [[Single protein]] structure of 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=2OP3 OCA].
__TOC__
 
</StructureSection>
==Reference==
Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode., Inagaki H, Tsuruoka H, Hornsby M, Lesley SA, Spraggon G, Ellman JA, J Med Chem. 2007 May 31;50(11):2693-9. Epub 2007 May 1. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17469812 17469812]
[[Category: Cathepsin S]]
[[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: Inagaki, H.]]
[[Category: Inagaki H]]
[[Category: Lesley, S A.]]
[[Category: Lesley SA]]
[[Category: Spraggon, G.]]
[[Category: Spraggon G]]
[[Category: Tsuruoka, H.]]
[[Category: Tsuruoka H]]
[[Category: cathepsin s]]
[[Category: nonpeptidic]]
[[Category: substrate activity screening]]
 
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Retrieved from "https://proteopedia.org/2op3"