4jt9

Crystal Structure of human SIRT3 with ELT inhibitor 3 [14-(4-{2-[(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide]

spinqualitylabelsall models 4jt9, resolution 2.24Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4jt9 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1NS, GOL, NA, ZN Related: 4jsr, 4jt8 Gene: SIRT3, SIR2L3 (Homo sapiens) Resources: FirstGlance, OCA, RCSB, PDBsum Function [SIR3_HUMAN] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels. Publication Abstract from PubMed The sirtuins SIRT1, SIRT2 and SIRT3 are NAD+ dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic and neurodegenerative disorders. Encoded Library Technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g. 11c: IC50 = 3.6, 2.7 and 4.0 nM for SIRT1, SIRT2 and SIRT3 respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogs 28 and 31. Crystallographic studies of 11c, 28 and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors which makes them valuable tools for sirtuin research. Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2 and SIRT3.,Disch JS, Evindar G, Chui CH, Blum CA, Dai H, Jin L, Schuman E, Lind KE, Belyanskaya SL, Deng J, Coppo FT, Aquilani L, Graybill TL, Cuozzo JW, Lavu S, Mao C, Vlasuk GP, Perni RB J Med Chem. 2013 Apr 9. PMID:23570514 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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