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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.
(2024)
.
- e202400273.
ISSN 1860-7187
DOI: https://doi.org/10.1002/cmdc.202400273
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.
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| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Keywords: | Acyl binding pocket; Crystal structure; DNA-encoded chemical libraries; Deacylase; Sirt6 inhibition |
| Institutionen der Universität: | Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie I - Proteinbiochemie der Signaltransduktion > Lehrstuhl Biochemie I - Proteinbiochemie der Signaltransduktion - Univ.-Prof. Dr. Clemens Steegborn |
| Titel an der UBT entstanden: | Ja |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik > 540 Chemie |
| Eingestellt am: | 16 Sep 2024 06:29 |
| Letzte Änderung: | 16 Sep 2024 06:29 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/90409 |