The
AMP-activated protein kinase (
AMPK) is an alphabetagamma heterotrimer that plays a pivotal role in regulating cellular and whole-body
metabolism.
Activation of
AMPK reverses many of the
metabolic defects associated with
obesity and
type 2 diabetes, and therefore
AMPK is considered a promising target for
drugs to treat these diseases. Recently, the thienopyridone A769662 has been reported to directly activate
AMPK by an unexpected mechanism. Here we show that A769662 activates
AMPK by a mechanism involving the beta
subunit carbohydrate-binding module and residues from the gamma
subunit but not the AMP-binding sites. Furthermore, A769662 exclusively activates
AMPK heterotrimers containing the beta1
subunit. Our findings highlight the regulatory role played by the beta
subunit in modulating
AMPK activity and the possibility of developing
isoform specific therapeutic activators of this important
metabolic regulator.
