Elucidating the Unconventional Binding Mode of a DNA‐Encoded Library Hit Provides a Blueprint for Sirtuin 6 Inhibitor Development

DOI zum Zitieren der Version auf EPub Bayreuth: https://doi.org/10.15495/EPub_UBT_00008289
URN to cite this document: urn:nbn:de:bvb:703-epub-8289-0

Title data

You, Weijie ; Montoya, Alba L. ; Dana, Srikanta ; Franzini, Raphael M. ; Steegborn, Clemens:
Elucidating the Unconventional Binding Mode of a DNA‐Encoded Library Hit Provides a Blueprint for Sirtuin 6 Inhibitor Development.
In: ChemMedChem. Vol. 19 (2024) Issue 20 . - e202400273.
ISSN 1860-7187
DOI der Verlagsversion: https://doi.org/10.1002/cmdc.202400273

	Format: PDF Name: ChemMedChem - 2024 - You - Elucidating the Unconventional Binding Mode of a DNA‐Encoded Library Hit Provides a Blueprint.pdf Version: Published Version Available under License Creative Commons BY-NC-ND 4.0: Attribution, Noncommercial, No Derivative Works
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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.

Further data

Item Type:	Article in a journal
Keywords:	Acyl binding pocket; Crystal structure; DNA-encoded chemical libraries; Deacylase; Sirt6 inhibition
DDC Subjects:	500 Science > 540 Chemistry
Institutions of the University:	Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry I - Proteinbiochemie der Signaltransduktion > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn Faculties Faculties > Faculty of Biology, Chemistry and Earth Sciences Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry I - Proteinbiochemie der Signaltransduktion
Language:	English
Originates at UBT:	Yes
URN:	urn:nbn:de:bvb:703-epub-8289-0
Date Deposited:	12 Mar 2025 06:10
Last Modified:	12 Mar 2025 06:11
URI:	https://epub.uni-bayreuth.de/id/eprint/8289

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