6HOY

Human Sirt6 in complex with ADP-ribose and the inhibitor trichostatin A

Summary for 6HOY

• Entry DOI: 10.2210/pdb6hoy/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-6, [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE, ZINC ION, ... (8 entities in total)
• Functional Keywords: deacylase, inhibitor, hydroxamate, non-competitive, isoform-selective, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 70364.47

Authors

You, W.,Steegborn, C. (deposition date: 2018-09-18, release date: 2018-11-14, Last modification date: 2024-01-24)

Primary citation

You, W.,Steegborn, C.
Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development.
J.Med.Chem., 61:10922-10928, 2018

PubMed 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.

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

Experimental method

X-RAY DIFFRACTION (1.7 Å)