| Title: | Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK alpha 2 beta 2 gamma 1 by the Glucose Importagog SC4 |
| Authors: | Ngoei, KRW Langendorf, CG Ling, NXY Hoque, A Varghese, S Camerino, MA Walker, SR Bozikis, YE Dite, TA Ovens, AJ Smiles, WJ Jacobs, R Huang, H Parker, MW Scott, JW Rider, MH Foitzik, RC Kemp, BE Baell, JB Oakhill, JS |
| Issue Year: | 2018 |
| Publisher | CELL PRESS |
| Series | Cell Chem. Biol.: |
| Abstract | The AMP-activated protein kinase (AMPK) alpha beta gamma het-erotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Smallmolecule activation of skeletal muscle alpha 2 beta 2 AMPK complexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-molecule SC4 is a potent, direct AMPK activator that preferentially activates alpha 2 complexes and stimulates skeletal muscle glucose uptake. In parallel with the term secretagog, we propose "importagog" to define a substance that induces or augments cellular uptake of another substance. Three-dimensional structures of the glucose importagog SC4 bound to activated alpha 2 beta 2 gamma 1 and alpha 2 beta 1 gamma 1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4'-nitrogen and beta 2-Asp111, which provide a design paradigm for beta 2-AMPK therapeutics. The alpha 2 beta 2 gamma 1/SC4 structure reveals an interaction between a beta 2 N-terminal alpha helix and the alpha 2 autoinhibitory domain. Our results provide a structurefunction guide to accelerate development of potent, but importantly tissue-specific, beta 2-AMPK therapeutics. |
| URI: | https://publications.svi.edu.au/publications/4467 |
| Other Identifiers | 10.1016/j.chembiol.2018.03.008 |
| Publication type | Article |