4FVT

Human SIRT3 bound to Ac-ACS peptide and Carba-NAD

Summary for 4FVT

• Entry DOI: 10.2210/pdb4fvt/pdb
• Related: 4G1C
• Descriptor: NAD-dependent protein deacetylase sirtuin-3, mitochondrial, Acetylated ACS2 peptide, CARBA-NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (7 entities in total)
• Functional Keywords: sirtuin, carba-nad, hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Mitochondrion matrix: Q9NTG7
• Total number of polymer chains: 2
• Total formula weight: 32206.05

Authors

Dai, H. (deposition date: 2012-06-29, release date: 2012-08-15, Last modification date: 2012-09-19)

Primary citation

Szczepankiewicz, B.G.,Dai, H.,Koppetsch, K.J.,Qian, D.,Jiang, F.,Mao, C.,Perni, R.B.
Synthesis of Carba-NAD and the Structures of Its Ternary Complexes with SIRT3 and SIRT5.
J.Org.Chem., 77:7319-7329, 2012

PubMed Abstract: Carba-NAD is a synthetic compound identical to NAD except for one substitution, where an oxygen atom adjacent to the anomeric linkage bearing nicotinamide is replaced with a methylene group. Because it is inert in nicotinamide displacement reactions, carba-NAD is an unreactive substrate analogue for NAD-consuming enzymes. SIRT3 and SIRT5 are NAD-consuming enzymes that are potential therapeutic targets for the treatment of metabolic diseases and cancers. We report an improved carba-NAD synthesis, including a pyrophosphate coupling method that proceeds in approximately 60% yield. We also disclose the X-ray crystal structures of the ternary complexes of SIRT3 and SIRT5 bound to a peptide substrate and carba-NAD. These X-ray crystal structures provide critical snapshots of the mechanism by which human sirtuins function as protein deacylation catalysts.

PubMed: 22849721
DOI: 10.1021/jo301067e

Experimental method

X-RAY DIFFRACTION (2.47 Å)