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

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  • Christopher G. Langendorf

    (Protein Chemistry & Metabolism, St Vincent’s Institute of Medical Research, University of Melbourne)

  • Kevin R. W. Ngoei

    (Protein Chemistry & Metabolism, St Vincent’s Institute of Medical Research, University of Melbourne)

  • John W. Scott

    (Protein Chemistry & Metabolism, St Vincent’s Institute of Medical Research, University of Melbourne)

  • Naomi X. Y. Ling

    (Metabolic Signaling Laboratory, St Vincent’s Institute of Medical Research, University of Melbourne)

  • Sam M. A. Issa

    (Protein Chemistry & Metabolism, St Vincent’s Institute of Medical Research, University of Melbourne
    Metabolic Signaling Laboratory, St Vincent’s Institute of Medical Research, University of Melbourne)

  • Michael A. Gorman

    (ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research, University of Melbourne)

  • Michael W. Parker

    (ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research, University of Melbourne)

  • Kei Sakamoto

    (Nestlé Institute of Health Sciences SA)

  • Jonathan S. Oakhill

    (Metabolic Signaling Laboratory, St Vincent’s Institute of Medical Research, University of Melbourne)

  • Bruce E. Kemp

    (Protein Chemistry & Metabolism, St Vincent’s Institute of Medical Research, University of Melbourne
    Mary MacKillop Institute for Health Research Australian Catholic University, Victoria Parade)

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.

Suggested Citation

  • Christopher G. Langendorf & Kevin R. W. Ngoei & John W. Scott & Naomi X. Y. Ling & Sam M. A. Issa & Michael A. Gorman & Michael W. Parker & Kei Sakamoto & Jonathan S. Oakhill & Bruce E. Kemp, 2016. "Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding," Nature Communications, Nature, vol. 7(1), pages 1-8, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10912
    DOI: 10.1038/ncomms10912
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