title: Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules.
abstract: Sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer. Activators are available for Sirt1 and exploit its unique N-terminus, whereas drug-like activators for Sirt2-7 are lacking. We synthesized and screened pyrrolo[1,2-a]quinoxaline derivatives, yielding the first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Our results establish potent Sirt6 activation with small molecules and provide a structural basis for further development of Sirt6 activators as tools and therapeutics.
authors.affiliation: Universität Bayreuth, Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle, Universitätsstr. 30, 95447, Bayreuth, Germany.
authors.forename: Weijie
authors.initials: W
authors.lastname: You
authors.affiliation: Sapienza University Roma, Department of Drug Chemistry and Technologies and Pasteur Institute of the Cenci-Bolognetti Foundation, P. le A. Moro 5, 00185, Rome, Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.affiliation: Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive Grant Bldg., Rm. S-025, Stanford, CA, 94305, USA.|Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
authors.forename: Tie-Mei
authors.initials: TM
authors.lastname: Li
authors.affiliation: Universität Bayreuth, Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle, Universitätsstr. 30, 95447, Bayreuth, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kambach
authors.affiliation: Abteilung Enzymology, Institut für Biochemie und Biotechnologie, Martin-Luther-Universität, Kurt-Mothes-Str. 3, 06110, Halle (Saale), Germany.
authors.forename: Marat
authors.initials: M
authors.lastname: Meleshin
authors.affiliation: Abteilung Enzymology, Institut für Biochemie und Biotechnologie, Martin-Luther-Universität, Kurt-Mothes-Str. 3, 06110, Halle (Saale), Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Schutkowski
authors.affiliation: Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive Grant Bldg., Rm. S-025, Stanford, CA, 94305, USA.|Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
authors.forename: Katrin F
authors.initials: KF
authors.lastname: Chua
authors.affiliation: Sapienza University Roma, Department of Drug Chemistry and Technologies and Pasteur Institute of the Cenci-Bolognetti Foundation, P. le A. Moro 5, 00185, Rome, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: Universität Bayreuth, Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle, Universitätsstr. 30, 95447, Bayreuth, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
mesh_terms: D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D011810:Quinoxalines / Q000737:chemistry / Q000378:metabolism*; D037761:Sirtuins / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011758:Pyrroles; D011810:Quinoxalines; D054852:Small Molecule Libraries; C531444:pyrrolo(1,2-a)quinoxaline; C516592:SIRT6 protein, human; D037761:Sirtuins
keywords: deacetylases; drug discovery; enzymes; sirtuin activators; structural biology