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Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release
Scott, John Galic, Sandra Graham, Kate Foitzik, Richard Ling, Naomi Dite, Toby Issa, Samah Langendorf, Chris Weng, Qing Thomas, Helen
Scott, John
Galic, Sandra
Graham, Kate
Foitzik, Richard
Ling, Naomi
Dite, Toby
Issa, Samah
Langendorf, Chris
Weng, Qing
Thomas, Helen
Abstract
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.
Keywords
Date
2015
Type
Journal article
Journal
Chemistry and Biology
Book
Volume
22
Issue
6
Page Range
705-711
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Non-faculty
Faculty of Health Sciences
Non-faculty
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Open Access Status
License
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Controlled