ArticlePloS one2015
Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2).
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 15 citations in OpenAlex.
- Bioactive fungal metabolites as SIRT2 antagonists: A computational quest for cancer treatment.PloS one · 2025Article
- Multifaceted regulation of sirtuin 2 (Sirt2) deacetylase activity.The Journal of biological chemistry · 2024Article
- MDFit: automated molecular simulations workflow enables high throughput assessment of ligands-protein dynamics.Journal of computer-aided molecular design · 2024Article
- Recent Advances in the Discovery of SIRT1/2 Inhibitors via Computational Methods: A Perspective.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors.International journal of molecular sciences · 2023Article
- In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents.Scientific reports · 2023Article
- Will Sirtuin 2 Be a Promising Target for Neuroinflammatory Disorders?Frontiers in cellular neuroscience · 2022Review
- Bioactivity Profiles of Cytoprotective Short-Chain Quinones.Molecules (Basel, Switzerland) · 2021Article
- Post-translational Lysine Ac(et)ylation in Bacteria: A Biochemical, Structural, and Synthetic Biological Perspective.Frontiers in microbiology · 2021Review
- Active nuclear import of the deacetylase Sirtuin-2 is controlled by its C-terminus and importins.Scientific reports · 2020Article
- SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases.Frontiers in pharmacology · 2020Review
- SIRT2 Inhibition Confers Neuroprotection by Downregulation of FOXO3a and MAPK Signaling Pathways in Ischemic Stroke.Molecular neurobiology · 2018Article
- Structural prediction of the interaction of the tumor suppressor p27BMC bioinformatics · 2017Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sirtuin 2 (SIRT2) is a NAD+-dependent deacetylase that has been associated with neurodegeneration and cancer. SIRT2 is composed of a central catalytic domain, the structure of which has been solved, and N- and C-terminal extensions that are thought to control SIRT2 function. However structural information of these N- and C-terminal regions is missing. Here, we provide the first full-length molecular models of SIRT2 in the absence and presence of NAD+. We also predict the structural alterations associated with phosphorylation of SIRT2 at S331, a modification that inhibits catalytic activity. Bioinformatics tools and molecular dynamics simulations, complemented by in vitro deacetylation assays, provide a consistent picture based on which the C-terminal region of SIRT2 is suggested to function as an autoinhibitory region. This has the capacity to partially occlude the NAD+ binding pocket or stabilize the NAD+ in a non-productive state. Furthermore, our simulations suggest that the phosphorylation at S331 causes large conformational changes in the C-terminal region that enhance the autoinhibitory activity, consistent with our previous findings that phosphorylation of S331 by cyclin-dependent kinases inhibits SIRT2 catalytic activity. The molecular insight into the role of the C-terminal region in controlling SIRT2 function described in this study may be useful for future design of selective inhibitors targeting SIRT2 for therapeutic applications.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.