Journal article

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

Christopher G Langendorf, Kevin RW Ngoei, John W Scott, Naomi XY Ling, Sam MA Issa, Michael A Gorman, Michael W Parker, Kei Sakamoto, Jonathan S Oakhill, Bruce E Kemp



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 metabol..

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Funding Acknowledgements

This research was partly undertaken on the MX2 beamline at the Australian Synchrotron, Victoria, Australia and we thank the beamline staff for their assistance. This work was supported by grants and fellowships from the Australian Research Council (ARC) and the National Health and Medical Research Council (NHMRC). Supported in part by the Victorian Government's Operational Infrastructure