2op3 | pdb_00002op3
The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method
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Overview
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 muM 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.
About this Structure
2OP3 is a Single protein structure of sequence from Homo sapiens with SO4, TF5 and PEU as ligands. Active as Cathepsin S, with EC number 3.4.22.27 Full crystallographic information is available from OCA.
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 1;. PMID:17469812
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