2. Academic Validation
  3. Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding

Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding

  • Nat Commun. 2016 Mar 8:7:10912. doi: 10.1038/ncomms10912.
Christopher G Langendorf 1,  Kevin R W Ngoei 1,  John W Scott 1,  Naomi X Y Ling 2,  Sam M A Issa 1 2,  Michael A Gorman 3,  Michael W Parker 3,  Kei Sakamoto 4,  Jonathan S Oakhill 2,  Bruce E Kemp 1 5
Affiliations

Affiliations

  • 1 Protein Chemistry &Metabolism, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
  • 2 Metabolic Signaling Laboratory, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
  • 3 ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
  • 4 Nestlé Institute of Health Sciences SA, EPFL Innovation Park, bâtiment G, 1015 Lausanne, Switzerland.
  • 5 Mary MacKillop Institute for Health Research Australian Catholic University, Victoria Parade, Fitzroy, Victoria 3065, Australia.
PMID: 26952388 DOI: 10.1038/ncomms10912
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.

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