| Title: | Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release |
| Authors: | Scott, JW Galic, S Graham, KL Foitzik, R Ling, NXY Dite, TA Issa, SMA Langendorf, CG Weng, QP Thomas, HE Kay, TW Birnberg, NC Steinberg, GR Kemp, BE Oakhill, JS |
| Issue Year: | 2015 |
| Publisher | CELL PRESS |
| Series | Chem. Biol.: |
| Abstract | The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing alpha beta gamma 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 beta 1 or beta 2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the beta 2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (Ile81, Phe91, Ile92), but was independent of beta 2-Ser108 phosphorylation. Whereas MT47-100 regulation of total cellular AMPK activity was determined by beta/beta 2 expression ratio, MT47-100 augmented glucose-stimulated insulin secretion from isolated mouse pancreatic islets via a beta 2-dependent mechanism. Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors. |
| URI: | https://publications.svi.edu.au/publications/2259 |
| ISSN | |
| Other Identifiers | 10.1016/j.chembiol.2015.05.011 |
| Publication type | Article |
| Grant ID | GNT1049197 |