1YC2

Sir2Af2-NAD-ADPribose-nicotinamide

Summary for 1YC2

• Entry DOI: 10.2210/pdb1yc2/pdb
• Descriptor: NAD-dependent deacetylase 2, ADENOSINE-5-DIPHOSPHORIBOSE, ZINC ION, ... (11 entities in total)
• Functional Keywords: sir2, sirtuin, nicotinamide, nad, adpribose, ternary complex, hydrolase
• Biological source: Archaeoglobus fulgidus
• Cellular location: Cytoplasm (Probable): O30124
• Total number of polymer chains: 5
• Total formula weight: 149541.70

Authors

Avalos, J.L.,Bever, M.K.,Wolberger, C. (deposition date: 2004-12-21, release date: 2005-03-29, Last modification date: 2024-02-14)

Primary citation

Avalos, J.L.,Bever, K.M.,Wolberger, C.
Mechanism of Sirtuin Inhibition by Nicotinamide: Altering the NAD(+) Cosubstrate Specificity of a Sir2 Enzyme.
Mol.Cell, 17:855-868, 2005

PubMed Abstract: Sir2 enzymes form a unique class of NAD(+)-dependent deacetylases required for diverse biological processes, including transcriptional silencing, regulation of apoptosis, fat mobilization, and lifespan regulation. Sir2 activity is regulated by nicotinamide, a noncompetitive inhibitor that promotes a base-exchange reaction at the expense of deacetylation. To elucidate the mechanism of nicotinamide inhibition, we determined ternary complex structures of Sir2 enzymes containing nicotinamide. The structures show that free nicotinamide binds in a conserved pocket that participates in NAD(+) binding and catalysis. Based on our structures, we engineered a mutant that deacetylates peptides by using nicotinic acid adenine dinucleotide (NAAD) as a cosubstrate and is inhibited by nicotinic acid. The characteristics of the altered specificity enzyme establish that Sir2 enzymes contain a single site that participates in catalysis and nicotinamide regulation and provides additional insights into the Sir2 catalytic mechanism.

PubMed: 15780941
DOI: 10.1016/j.molcel.2005.02.022

Experimental method

X-RAY DIFFRACTION (2.4 Å)