Mechanism and cellular actions of the potent AMPK inhibitor BAY-3827.

ABSTRACT: Inhibition of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is under increasing investigation for its therapeutic potential in many diseases. Existing AMPK inhibitors are however limited, with poor selectivity and substantial off-target effects. Here, we provide mechanistic insights and describe the cellular selectivity of the recently identified AMPK inhibitor BAY-3827. A 2.5-Å cocrystal structure of the AMPK kinase domain with BAY-3827 revealed distinct features including a disulfide bridge between the αD helix Cys106 and the activation loop residue Cys174. This bridge appears to stabilize the activation loop such that Asn162 repositions the Asp-Phe-Gly (DFG) motif Phe158 toward the C-terminal lobe, displacing His137 and disrupting the regulatory spine, promoting an in

SUBMITTER: Bringas CF 

PROVIDER: S-EPMC12372887 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature