4i5i

Crystal structure of the SIRT1 catalytic domain bound to NAD and an EX527 analog

spinqualitylabelsall models 4i5i, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4i5i is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4I5, NAD, ZN Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed The sirtuin SIRT1 is a NAD(+)-dependent histone deacetylase, a Sir2 family member, and one of seven human sirtuins. Sirtuins are conserved from archaea to mammals and regulate transcription, genome stability, longevity, and metabolism. SIRT1 regulates transcription via deacetylation of transcription factors such as PPARgamma, NFkappaB, and the tumor suppressor protein p53. EX527 (27) is a nanomolar SIRT1 inhibitor and a micromolar SIRT2 inhibitor. To elucidate the mechanism of SIRT inhibition by 27, we determined the 2.5 A crystal structure of the SIRT1 catalytic domain (residues 241-516) bound to NAD(+) and the 27 analogue compound 35. 35 binds deep in the catalytic cleft, displacing the NAD(+) nicotinamide and forcing the cofactor into an extended conformation. The extended NAD(+) conformation sterically prevents substrate binding. The SIRT1/NAD(+)/35 crystal structure defines a novel mechanism of histone deacetylase inhibition and provides a basis for understanding, and rationally improving, inhibition of this therapeutically important target by drug-like molecules. The 2.5 A crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition.,Zhao X, Allison D, Condon B, Zhang F, Gheyi T, Zhang A, Ashok S, Russell M, MacEwan I, Qian Y, Jamison JA, Luz JG J Med Chem. 2013 Feb 14;56(3):963-9. doi: 10.1021/jm301431y. Epub 2013 Jan 29. PMID:23311358 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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