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Updated: May 13, 2026

Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates
14:32

Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates

Published on: February 27, 2016

Insight the C-site pocket conformational changes responsible for sirtuin 2 activity using molecular dynamics

Sugunadevi Sakkiah1, Mahreen Arooj, Guang Ping Cao

  • 1Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Research Institute of Natural Science (RINS), Gyeongsang National University, Jinju, South Korea.

Plos One
|March 26, 2013
PubMed

Insights

Sirtuin 2 (SIRT2) deacetylation activity is regulated by conformational changes in its catalytic site, influenced by substrate/NAD(+) and inhibitors. Understanding these structural dynamics can enhance SIRT2 inhibitor development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Sirtuins are NAD(+)-dependent deacetylases regulating critical cellular processes.
  • SIRT2 mutations (Q167A, H187A) reduce activity, but structural basis remains unclear.

Purpose of the Study:

  • To investigate the structural dynamics of wild-type (WT) and mutant SIRT2.
  • To elucidate the role of substrate/NAD(+) and inhibitors in SIRT2 structural changes.

Main Methods:

  • 5 ns molecular dynamics (MD) simulations of SIRT2 Apo-form.
  • MD simulations of WT, Q167A, and H187A SIRT2 complexes with substrate/NAD(+) and inhibitor.

Main Results:

  • Substrate/NAD(+) binding induces C-site assembly, while inhibitor binding causes disassembly.
  • Interactions involving F96 and the F96-H187 distance are key to C-site dynamics.
  • Conformational changes in the L3 loop significantly impact C-site assembly/disassembly.

Conclusions:

  • Distinct L3 loop conformational changes and C-site dynamics are crucial for SIRT2 deacetylation.
  • Elucidating SIRT2 structural changes aids in improving the potency of SIRT2 inhibitors.

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