2h7j: Difference between revisions

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[[Image:2h7j.jpg|left|200px]]
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[[Image:2h7j.png|left|200px]]


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{{STRUCTURE_2h7j|  PDB=2h7j  |  SCENE=  }}  
{{STRUCTURE_2h7j|  PDB=2h7j  |  SCENE=  }}  


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




==Overview==
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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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{{ABSTRACT_PUBMED_17034136}}


==About this Structure==
==About this Structure==
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[[Category: Nonpeptidic]]
[[Category: Nonpeptidic]]
[[Category: Substrate activity screening]]
[[Category: Substrate activity screening]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 05:57:45 2008''
 
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Revision as of 00:14, 29 July 2008

File:2h7j.png

Template:STRUCTURE 2h7j

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

Template:ABSTRACT PUBMED 17034136

About this Structure

2H7J is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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

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