AMP-activated protein kinase (AMPK), an αβγ heterotrimer, is a central regulator of cellular and whole body energy metabolism. AMPK responds to reductions in adenylate energy charge (increased ADP/ATP and AMP/ATP ratios) by directing the metabolic focus of the cell towards catabolic, energy producing processes. Recent evidence implicating AMPK as a drug target to treat obesity-related metabolic diseases, as well as cancer and neurodegenerative diseases, has sparked great interest in developing AMPK direct activators.

We recently showed that A769662, the first described synthetic AMPK direct activator, specifically activates AMPK complexes containing the β1-isoform. We have since characterised a novel class of small molecule direct AMPK activators (typified by MT47-100) as dual β1-specific activators/β2-specific inhibitors. Using targetted mutagenesis of recombinant AMPK we found that β-isoform selectivity of A769662 and MT47-100 is conferred entirely by three residues (β1-F82, Y91 and L92) located in the β-subunit carbohydrate binding module. These findings provide important clues regarding the location of the drug binding site on AMPK.