DRUG DISCOVERY Allosteric Site Inhibitors for Caspases

The active sites of proteins with enzymatic activity are not always suitable for drug targeting. Hardy et al. report the application of a method called "Tethering" to identify an allosteric site inhibitor on the executioner caspases, caspase-3. Tethering, a commercial method, uses reversible disulfide bond formation to identify accessible cysteines that can interact with a library of thiol-containing compounds. The two compounds (DICA and FICA) bound a conserved cysteine in a cavity at the caspase dimer interface. This cysteine is also present in caspase-7, and the two inhibitors bound and inhibited the catalytic activity of both caspase-3 and -7. Analysis of crystal structures of caspase-7 with the inhibitors showed that the two inhibitors bound in different orientations to the caspase but induced the same conformational change in the protein. The inhibitors induced a zymogen-like (procaspase-like) conformation to the cleaved and activated caspase. The cavity where the two inhibitors bound is also seen in other caspases, like initiator and inflammatory caspases. Thus, the authors speculate that this domain may serve as an allosteric site for an as yet unidentified native regulator.

J. A. Hardy, J. Lam, J. T. Nguyen, T. O'Brien, J. A. Wells, Discovery of an allosteric site in the caspases. Proc. Natl. Acad. Sci. U.S.A. 101, 12461-12466 (2004). [Abstract] [Full Text]

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