Sanguinarine is an allosteric activator of AMP-activated protein kinase

► We found that a natural product, Sanguinarine, directly bound and activated AMPK. ► Sanguinarine showed unique isotype selectivity in its activation effect. ► The allosteric mechanism of Sanguinarine was distinct from that of the natural ligand, AMP. ► A docking study predicts that Sanguinarine binds at the cleft between the beta and gamma subunits.