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Crystal structures of sirtuin 1 (SIRT1), SIRT2 and SIRT3 bound to inhibitors

Crystal structures of sirtuins bound to inhibitors could guide the development of compounds directed against specific sirtuins. Crystal structures of a SIRT1 inhibitor bound to SIRT1, SIRT3 or a bacterial Sirt2 showed the compound co-occupied a conserved pocket alongside the enzyme's catalytic product, thereby preventing product release. The co-crystal structures also showed no structural differences between the conserved pockets of the three sirtuins that could account for their differing binding affinities for the inhibitor. Crystal structures of a SIRT3 inhibitor bound to SIRT3 showed the compound simultaneously occupied the acetyllysine binding site and the conserved pocket. Ongoing work includes using the structural data to develop specific inhibitors of SIRT3.

SciBX 6(31); doi:10.1038/scibx.2013.841
Published online Aug. 15, 2013

Unpatented; unlicensed; available for partnering

Gertz, M. et al. Proc. Natl. Acad. Sci. USA; published online July 9, 2013;
doi:10.1073/pnas.1303628110
Nguyen, G.T.T. et al. Acta Crystallogr. D. Biol. Crystallogr.; published online
July 17, 2013;
doi:10.1107/S0907444913015448
Contact: Clemens Steegborn, University of Bayreuth, Bayreuth, Germany
e-mail:

clemens.steegborn@uni-bayreuth.de