2h7j
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(New page: 200px<br /> <applet load="2h7j" size="450" color="white" frame="true" align="right" spinBox="true" caption="2h7j, resolution 1.50Å" /> '''Crystal Structure o...)
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Revision as of 20:21, 12 November 2007
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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 with H7J and P15 as ligands. Active as Cathepsin S, with EC number 3.4.22.27 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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