7bot | pdb_00007bot
Human SIRT2 in complex with myristoyl thiourea inhibitor, No.23
Structural highlights
FunctionSIR2_HUMAN NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.[1] [2] [3] [4] Publication Abstract from PubMedSirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to well-characterized and robust tool compounds is essential for the continued investigation of the complex functions of this enzyme. Here, we report a collection of chemical probes that are potent, selective, stable in serum, water-soluble, and inhibit SIRT2-mediated deacetylation and demyristoylation in cells. Compared to the current landscape of SIRT2 inhibitors, this is a unique ensemble of features built into a single compound. We expect the developed chemotypes to find broad application in the interrogation of SIRT2 functions in both healthy and diseased cells, and to provide a foundation for the development of future therapeutics. Mechanism-based inhibitors of SIRT2: structure-activity relationship, X-ray structures, target engagement, regulation of alpha-tubulin acetylation and inhibition of breast cancer cell migration.,Nielsen AL, Rajabi N, Kudo N, Lundo K, Moreno-Yruela C, Baek M, Fontenas M, Lucidi A, Madsen AS, Yoshida M, Olsen CA RSC Chem Biol. 2021 Jan 14;2(2):612-626. doi: 10.1039/d0cb00036a. eCollection , 2021 Apr 1. PMID:34458803[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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