title: Structural basis of AMPK regulation by small molecule activators.
abstract: AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphorylation of threonine 172 within the activation loop of the kinase. AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number of direct AMPK activators have been reported as having beneficial effects in treating metabolic diseases, but there has been no structural basis for activator binding to AMPK. Here we present the crystal structure of human AMPK in complex with a small molecule activator that binds at a site between the kinase domain and the carbohydrate-binding module, stabilising the interaction between these two components. The nature of the activator-binding pocket suggests the involvement of an additional, as yet unidentified, metabolite in the physiological regulation of AMPK. Importantly, the structure offers new opportunities for the design of small molecule activators of AMPK for treatment of metabolic disorders.
authors.affiliation: 1] MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK [2].
authors.forename: Bing
authors.initials: B
authors.lastname: Xiao
authors.affiliation: 1] MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK [2].
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sanders
authors.affiliation: 1] MRC Clinical Sciences Centre, Cellular Stress Group, Hammersmith Hospital Campus, Imperial College, DuCane Road, London W12 0NN, UK [2].
authors.forename: David
authors.initials: D
authors.lastname: Carmena
authors.affiliation: MRC Clinical Sciences Centre, Cellular Stress Group, Hammersmith Hospital Campus, Imperial College, DuCane Road, London W12 0NN, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Bright
authors.affiliation: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Lesley F
authors.initials: LF
authors.lastname: Haire
authors.affiliation: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Underwood
authors.affiliation: MRC Clinical Sciences Centre, Cellular Stress Group, Hammersmith Hospital Campus, Imperial College, DuCane Road, London W12 0NN, UK.
authors.forename: Bhakti R
authors.initials: BR
authors.lastname: Patel
authors.affiliation: 1] MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK [2].
authors.forename: Richard B
authors.initials: RB
authors.lastname: Heath
authors.affiliation: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Walker
authors.affiliation: Bioscience, CVMD Innovative Medicine Unit, AstraZeneca R&D, Pepparedsleden 1, Mölndal S-43183, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hallen
authors.affiliation: 1] Medicinal Chemistry, CVMD Innovative Medicine Unit, AstraZeneca R&D, Pepparedsleden 1, Mölndal S-43183, Sweden [2].
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.affiliation: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Martin
authors.affiliation: MRC Clinical Sciences Centre, Cellular Stress Group, Hammersmith Hospital Campus, Imperial College, DuCane Road, London W12 0NN, UK.
authors.forename: David
authors.initials: D
authors.lastname: Carling
authors.affiliation: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gamblin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry*; D000249:Adenosine Monophosphate / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000495:Allosteric Site; D001665:Binding Sites; D002241:Carbohydrates / Q000737:chemistry; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D007368:Interferometry; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D013912:Threonine / Q000737:chemistry
chemical_list: D002241:Carbohydrates; D011994:Recombinant Proteins; D013912:Threonine; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases