AMP-activated protein kinase (AMPK) is a key metabolic regulator involved in sensing and responding to changes in the energetic state of the cell.  As such, activation of AMPK has emerged as a therapeutic target for the treatment of metabolic disorders.  AMPK functions as a heterotrimeric serine/threonine kinase comprised of a catalytic α subunit in complex with regulatory β and γ subunits.  The presence of multiple gene products for each of these subunits permits the existence of multiple AMPK isoforms differing in function and tissue distribution. <br/>Starting from high throughput screening, we have identified and optimized a novel allosteric series.  Interestingly, compounds potently activate heterotrimeric AMPK, but have no effects on the functional activity of isolated kinase domain, raising the possible involvement of regulatory domains in ligand binding.  Using a combination of biochemistry, enzymology, and structural biology, we characterize the mode and mechanism of AMPK modulation by this series.

Allosteric activators of AMP-activated protein kinase (AMPK)

ACS Spring 2022

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