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[[Image:2op3.jpg|left|200px]]
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{{STRUCTURE_2op3|  PDB=2op3  |  SCENE=  }}
'''The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method'''


==The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method==
<StructureSection load='2op3' size='340' side='right'caption='[[2op3]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<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>
</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>
<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>
<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>
</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/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.


==Overview==
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>
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.


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


==Reference==
==See Also==
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]
*[[Cathepsin 3D structures|Cathepsin 3D structures]]
[[Category: Cathepsin S]]
== 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: 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]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 11:22:01 2008''

Latest revision as of 12:46, 25 December 2024

The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) methodThe structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method

Structural highlights

2op3 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.6Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

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 >1000-fold selectivity relative to cathepsins B, L, and K.

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[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Inagaki H, Tsuruoka H, Hornsby M, Lesley SA, Spraggon G, Ellman JA. Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode. J Med Chem. 2007 May 31;50(11):2693-9. Epub 2007 May 1. PMID:17469812 doi:http://dx.doi.org/10.1021/jm070111+

2op3, resolution 1.60Å

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