Structural Determinants For Small-Molecule Activation Of Skeletal Muscle Ampk Alpha 2 Beta 2 Gamma 1 By The Glucose Importagog Sc4

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.