title: Crystal structures of SIRT3 reveal that the α2-α3 loop and α3-helix affect the interaction with long-chain acyl lysine.
abstract: SIRT1-7 play important roles in many biological processes and age-related diseases. In addition to a NAD(+) -dependent deacetylase activity, they can catalyze several other reactions, including the hydrolysis of long-chain fatty acyl lysine. To study the binding modes of sirtuins to long-chain acyl lysines, we solved the crystal structures of SIRT3 bound to either a H3K9-myristoylated- or a H3K9-palmitoylated peptide. Interaction of SIRT3 with the palmitoyl group led to unfolding of the α3-helix. The myristoyl and palmitoyl groups bind to the C-pocket and an allosteric site near the α3-helix, respectively. We found that the residues preceding the α3-helix determine the size of the C-pocket. The flexibility of the α2-α3 loop and the plasticity of the α3-helix affect the interaction with long-chain acyl lysine.
authors: Department of Pharmacology III, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.|University of Chinese Academy of Sciences, Beijing, China.
authors: Wei
authors: W
authors: Gai
authors: University of Chinese Academy of Sciences, Beijing, China.|Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
authors: He
authors: H
authors: Li
authors: University of Chinese Academy of Sciences, Beijing, China.|Drug Design and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
authors: Hualiang
authors: H
authors: Jiang
authors: University of Chinese Academy of Sciences, Beijing, China.|Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
authors: Yaqiu
authors: Y
authors: Long
authors: Department of Pharmacology III, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.|University of Chinese Academy of Sciences, Beijing, China.
authors: Dongxiang
authors: D
authors: Liu
mesh_terms: D000215:Acylation; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D006801:Humans; D006868:Hydrolysis; D008239:Lysine / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D000072756:Protein Conformation, alpha-Helical; D056566:Sirtuin 3 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010455:Peptides; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D008239:Lysine
keywords: allosteric site; deacylation; inhibitor; long-chain fatty acid; sirtuins