1S7G

Structural Basis for the Mechanism and Regulation of Sir2 Enzymes

Summary for 1S7G

• Entry DOI: 10.2210/pdb1s7g/pdb
• Descriptor: NAD-dependent deacetylase 2, ADENOSINE-5-DIPHOSPHORIBOSE, ZINC ION, ... (11 entities in total)
• Functional Keywords: enzyme, sirtuin, sir2, nad+, adp-ribose, transcription
• Biological source: Archaeoglobus fulgidus
• Cellular location: Cytoplasm (Probable): O30124
• Total number of polymer chains: 5
• Total formula weight: 148485.81

Authors

Avalos, J.L.,Boeke, J.D.,Wolberger, C. (deposition date: 2004-01-29, release date: 2004-03-23, Last modification date: 2023-08-23)

Primary citation

Avalos, J.L.,Boeke, J.D.,Wolberger, C.
Structural basis for the mechanism and regulation of sir2 enzymes
Mol.Cell, 13:639-648, 2004

PubMed Abstract: Sir2 proteins form a family of NAD(+)-dependent protein deacetylases required for diverse biological processes, including transcriptional silencing, suppression of rDNA recombination, control of p53 activity, regulation of acetyl-CoA synthetase, and aging. Although structures of Sir2 enzymes in the presence and absence of peptide substrate or NAD(+) have been determined, the role of the enzyme in the mechanism of deacetylation and NAD(+) cleavage is still unclear. Here, we present additional structures of Sir2Af2 in several differently complexed states: in a productive complex with NAD(+), in a nonproductive NAD(+) complex with bound ADP-ribose, and in the unliganded state. We observe a new mode of NAD(+) binding that seems to depend on acetyl-lysine binding, in which the nicotinamide ring of NAD(+) is buried in the highly conserved "C" pocket of the enzyme. We propose a detailed structure-based mechanism for deacetylation and nicotinamide inhibition of Sir2 consistent with mutagenesis and enzymatic studies.

PubMed: 15023335
DOI: 10.1016/S1097-2765(04)00082-6

Experimental method

X-RAY DIFFRACTION (2.3 Å)