Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development

Weijie You; Clemens Steegborn

doi:10.1021/acs.jmedchem.8b01455

Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development

J Med Chem. 2018 Dec 13;61(23):10922-10928. doi: 10.1021/acs.jmedchem.8b01455. Epub 2018 Nov 15.

Authors

Weijie You¹, Clemens Steegborn¹

Affiliation

¹ Department of Biochemistry , University of Bayreuth , Universitätsstraße 30 , 95445 Bayreuth , Germany.

PMID: 30395713
DOI: 10.1021/acs.jmedchem.8b01455

Abstract

Protein lysine deacylases comprise three zinc-dependent families and the NAD⁺-dependent sirtuins Sirt1-7, which contribute to aging-related diseases. Few Sirt6-specific inhibitors are available. Trichostatin A, which belongs to the potent, zinc-chelating hydroxamate inhibitors of zinc-dependent deacylases, was recently found to potently and isoform-specifically inhibit Sirt6. We solved a crystal structure of a Sirt6/ADP-ribose/trichostatin A complex, which reveals nicotinamide pocket and acyl channel as binding site and provides interaction details supporting the development of improved deacylase inhibitors.

MeSH terms

Drug Discovery*
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology*
Hydroxamic Acids / chemistry*
Hydroxamic Acids / pharmacology*
Models, Molecular
Protein Conformation
Sirtuins / antagonists & inhibitors*
Sirtuins / chemistry

Substances

Histone Deacetylase Inhibitors
Hydroxamic Acids
trichostatin A
Sirtuins