| First Author | Ngoei KRW | Year | 2018 |
| Journal | Cell Chem Biol | Volume | 25 |
| Issue | 6 | Pages | 728-737.e9 |
| PubMed ID | 29657085 | Mgi Jnum | J:320114 |
| Mgi Id | MGI:6869953 | Doi | 10.1016/j.chembiol.2018.03.008 |
| Citation | Ngoei KRW, et al. (2018) Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK alpha2beta2gamma1 by the Glucose Importagog SC4. Cell Chem Biol 25(6):728-737.e9 |
| abstractText | The AMP-activated protein kinase (AMPK) alphabetagamma heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle alpha2beta2 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 alpha2 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 alpha2beta2gamma1 and alpha2beta1gamma1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4'-nitrogen and beta2-Asp111, which provide a design paradigm for beta2-AMPK therapeutics. The alpha2beta2gamma1/SC4 structure reveals an interaction between a beta2 N-terminal alpha helix and the alpha2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, beta2-AMPK therapeutics. |
