title: Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding.
abstract: The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.
authors.affiliation: Protein Chemistry &Metabolism, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Langendorf
authors.affiliation: Protein Chemistry &Metabolism, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Kevin R W
authors.initials: KRW
authors.lastname: Ngoei
authors.affiliation: Protein Chemistry &Metabolism, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: John W
authors.initials: JW
authors.lastname: Scott
authors.affiliation: Metabolic Signaling Laboratory, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Naomi X Y
authors.initials: NXY
authors.lastname: Ling
authors.affiliation: Protein Chemistry &Metabolism, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.|Metabolic Signaling Laboratory, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Sam M A
authors.initials: SMA
authors.lastname: Issa
authors.affiliation: ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gorman
authors.affiliation: ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.affiliation: Nestlé Institute of Health Sciences SA, EPFL Innovation Park, bâtiment G, 1015 Lausanne, Switzerland.
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Metabolic Signaling Laboratory, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Oakhill
authors.affiliation: Protein Chemistry &Metabolism, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.|Mary MacKillop Institute for Health Research Australian Catholic University, Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000494:Allosteric Regulation; D001665:Binding Sites; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D063065:Organophosphonates / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation
chemical_list: C000610714:5-(5-hydroxylisoxazol-3-yl)furan-2-phosphonic acid; D020536:Enzyme Activators; D007555:Isoxazoles; D063065:Organophosphonates; D055372:AMP-Activated Protein Kinases