1gmy

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spinqualitylabelsall models 1gmy, resolution 1.9Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CATHEPSIN B COMPLEXED WITH DIPEPTIDYL NITRILE INHIBITOR

Overview

Cathepsin B is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. As part of an effort to identify potent, reversible inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH(2)CN (19, IC(50) = 62 microM). High-resolution X-ray crystallographic data and molecular modeling were used to optimize the P(1), P(2), and P(3) substituents of this template. Cathepsin B is unique in its class in that it contains a carboxylate recognition site in the S(2)' pocket of the active site. Inhibitor potency and selectivity were enhanced by tethering a carboxylate functionality from the carbon alpha to the nitrile to interact with this region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine cathepsins.

About this Structure

1GMY is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Active as Cathepsin B, with EC number 3.4.22.1 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design., Greenspan PD, Clark KL, Tommasi RA, Cowen SD, McQuire LW, Farley DL, van Duzer JH, Goldberg RL, Zhou H, Du Z, Fitt JJ, Coppa DE, Fang Z, Macchia W, Zhu L, Capparelli MP, Goldstein R, Wigg AM, Doughty JR, Bohacek RS, Knap AK, J Med Chem. 2001 Dec 20;44(26):4524-34. PMID:11741472

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