Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release

John W Scott, Sandra Galic, Kate L Graham, Richard Foitzik, Naomi X Y Ling, Toby A Dite, Samah M A Issa, Chris G Langendorf, Qing Ping Weng, Helen E Thomas, Thomas W Kay, Neal C Birnberg, Gregory R Steinberg, Bruce E Kemp, Jonathan S Oakhill

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47 Citations (Scopus)


The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis. Pharmacological inhibition of AMPK is regarded as a therapeutic strategy in some disease settings including obesity and cancer; however, the broadly used direct AMPK inhibitor compound C suffers from poor selectivity. We have discovered a dihydroxyquinoline drug (MT47-100) with novel AMPK regulatory properties, being simultaneously a direct activator and inhibitor of AMPK complexes containing the β1 or β2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the β2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (Ile81, Phe91, Ile92), but was independent of β2-Ser108 phosphorylation. Whereas MT47-100 regulation of total cellular AMPK activity was determined by β1/β2 expression ratio, MT47-100 augmented glucose-stimulated insulin secretion from isolated mouse pancreatic islets via a β2-dependent mechanism. Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors.
Original languageEnglish
Pages (from-to)705-711
Number of pages7
JournalChemistry and Biology
Issue number6
Publication statusPublished - 2015

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