9G7H

Human Sirt6 in complex with ADP-ribose and the inhibitor 2-Pr

This is a non-PDB format compatible entry.

Summary for 9G7H

• Entry DOI: 10.2210/pdb9g7h/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, ... (6 entities in total)
• Functional Keywords: deacylase, inhibitor, dna-encoded chemical libraries, acyl binding pocket, aging, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69726.60

Authors

You, W.,Steegborn, C. (deposition date: 2024-07-21, release date: 2024-08-14, Last modification date: 2024-10-30)

Primary citation

You, W.,Montoya, A.L.,Dana, S.,Franzini, R.M.,Steegborn, C.
Elucidating the Unconventional Binding Mode of a DNA-Encoded Library Hit Provides a Blueprint for Sirtuin 6 Inhibitor Development.
Chemmedchem, 19:e202400273-e202400273, 2024

PubMed Abstract: Sirtuin 6 (Sirt6), an NAD+-dependent deacylase, has emerged as a promising target for aging-related diseases and cancer. Advancing the medicinal chemistry of Sirt6 modulators is crucial for the development of chemical probes aimed at unraveling the intricate biological functions of Sirt6 and unlocking its therapeutic potential. A proprietary DNA-encoded library yielded Sirt6 inhibitor 2-Pr, displaying remarkable inhibitory activity and isoform-selectivity, and featuring a chemical structure distinct from reported Sirt6 modulators. In this study, we explore the inhibitory mechanism of 2-Pr, evaluating the impact of chemical modifications and presenting a crystal structure of the Sirt6/ADP-ribose/2-Pr complex. Notably, co-crystal structure analysis reveals an unexpected and unprecedented binding mode of Sirt6, with 2-Pr spanning the acyl channel of the enzyme, extending into the acetyl-lysine binding pocket, and reaching toward the C-site. This unique binding mode guides potential avenues for developing potent and selective Sirt6 inhibitors.

PubMed: 38940296
DOI: 10.1002/cmdc.202400273

Experimental method

X-RAY DIFFRACTION (1.75 Å)