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Related Concept Videos

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For successful DNA replication, the unwinding of double-stranded DNA must be accompanied by stabilization and protection of the separated single strands of the DNA. This crucial task is performed by single-strand DNA-binding (SSB) proteins. They bind to the DNA in a sequence-independent manner, which means that the nitrogenous bases of the DNA need not be present in a specific order for binding of SSB proteins to it. The binding of SSB proteins straightens single-stranded DNA (ssDNA) and makes...
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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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Elucidating the Unconventional Binding Mode of a DNA-Encoded Library Hit Provides a Blueprint for Sirtuin 6 Inhibitor

Weijie You1,2, Alba L Montoya3, Srikanta Dana3,4

  • 1Department of Biochemistry, University of Bayreuth, Universitaetsstr. 30, 95447, Bayreuth, Germany.

Chemmedchem
|June 28, 2024
PubMed
Summary

Sirtuin 6 (Sirt6) inhibitor 2-Pr shows unique binding, offering new strategies for developing targeted therapies for aging and cancer. This discovery advances medicinal chemistry for Sirt6 modulators.

Keywords:
Acyl binding pocketCrystal structureDNA-encoded chemical librariesDeacylaseSirt6 inhibition

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Sirtuin 6 (Sirt6) is a key NAD+-dependent deacylase implicated in aging and cancer.
  • Developing selective Sirt6 modulators is essential for therapeutic intervention and biological research.
  • Existing Sirt6 modulators lack distinct chemical scaffolds.

Purpose of the Study:

  • To investigate the inhibitory mechanism of a novel Sirt6 inhibitor, 2-Pr.
  • To explore structure-activity relationships through chemical modifications of 2-Pr.
  • To elucidate the binding mode of 2-Pr with Sirt6 via co-crystal structure analysis.

Main Methods:

  • Utilized a DNA-encoded library to identify Sirt6 inhibitor 2-Pr.
  • Performed biochemical assays to assess inhibitory activity and isoform-selectivity.
  • Determined the co-crystal structure of the Sirt6/ADP-ribose/2-Pr complex.

Main Results:

  • Identified 2-Pr, a potent and isoform-selective Sirtuin 6 inhibitor with a novel chemical structure.
  • The co-crystal structure revealed an unprecedented binding mode where 2-Pr occupies the acyl channel and extends into the acetyl-lysine binding pocket.
  • Chemical modifications of 2-Pr were evaluated, providing insights into structure-activity relationships.

Conclusions:

  • The unique binding mode of 2-Pr provides a novel structural basis for designing next-generation Sirt6 inhibitors.
  • This study opens new avenues for developing potent and selective Sirt6-targeted therapeutics for aging-related diseases and cancer.
  • The findings contribute to a deeper understanding of Sirtuin 6 enzymatic function and modulation.