Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4

Summary The AMP-activated protein kinase( AMPK) αβγ heterotrimer regulates cellular energy homeostasiswith tissue-specific isoform distribution. Small-moleculeactivation of skeletal muscle α2β2 AMPKcomplexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-moleculeSC4 is a potent, direct AMPKactivator that preferentially activates α2 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 α2β2γ1 and α2β1γ1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine4′-nitrogen and β2-Asp111, which provide a design paradigmfor β2- AMPKtherapeutics. The α2β2γ1/SC4 structure reveals an interaction between a β2 N-terminal α helix and the α2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, β2- AMPKtherapeutics.