2h7j
From Proteopedia
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'''Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.''' | '''Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.''' | ||
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[[Category: Spraggon, G.]] | [[Category: Spraggon, G.]] | ||
[[Category: Wood, W J.]] | [[Category: Wood, W J.]] | ||
| - | [[Category: | + | [[Category: Cathepsin s]] |
| - | [[Category: | + | [[Category: Chloromethylketone]] |
| - | [[Category: | + | [[Category: Nonpeptidic]] |
| - | [[Category: | + | [[Category: Substrate activity screening]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 05:57:45 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 02:57, 4 May 2008
Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.
Overview
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.
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 Page seeded by OCA on Sun May 4 05:57:45 2008
