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2op3
From Proteopedia
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The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method
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 , and 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
Page seeded by OCA on Wed Jan 23 13:56:50 2008
Categories: Cathepsin S | Homo sapiens | Single protein | Ellman, J.A. | Hornsby, M. | Inagaki, H. | Lesley, S.A. | Spraggon, G. | Tsuruoka, H. | PEU | SO4 | TF5 | Cathepsin s | Nonpeptidic | Substrate activity screening
