Mechanism and cellular actions of the potent AMPK inhibitor BAY-3827
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PROVIDER: PRJNA1225752 | ENA |
REPOSITORIES: ENA
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Project description:Inhibition of AMP-activated protein kinase (AMPK) is increasingly being explored for its therapeutic potential in some diseases, including certain types of cancers. However, AMPK-inhibitory tool compounds have largely been limited to compound C/dorsomorphin and SBI-0206965, both of which display numerous off-target effects and blocking AMPK-independent metabolic processes. Here we describe molecular insights and cellular actions/utility of a recently identified potent AMPK inhibitor BAY-3827. Sequence analysis of highly/lowly-inhibited kinases by BAY-3827, based on in vitro kinase selectivity profiling, predicted key conserved residues involved in the compound-inhibitory effect. A co-crystal structure of the AMPK kinase domain (KD)-BAY-3827 complex resolved at 2.5 Å in comparison with previously reported KD-inhibitor structures, revealed an overlapping binding site in the ATP-binding pocket and common αC helix-out conformations. We identified distinct features of BAY-3827-bound structure which involve a disulfide bridge between αD helix Cys106 and activation loop residue Cys174. This may help to stabilize AMPK conformation upon BAY-3827 binding, where the position of activation loop Asn162 leads the DFG motif Phe158 to adopt a conformation facing the C-terminal kinase lobe displacing His137, leading to a broken regulatory spine and an inactive kinase state. BAY-3827 at 2.5-5 μM, but not structurally resembling inactive BAY-974, fully blocked AMPK activator (MK-8722)-mediated phosphorylation of ACC1 and inhibition of lipogenesis in hepatocytes. Unbiased transcriptome analysis in MK-8722-treated wild-type and AMPK-null hepatocytes revealed that >30% of MK-8722-stimulated AMPK-dependent genes could be downregulated by 5 μM BAY-3827. Based on its greater selectivity and potency substantiated by comprehensive molecular/cellular investigations. BAY-3827 is a powerful tool to delineate AMPK functions.
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Project description:Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, while AMPK is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive GILZ, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Since increased action of glucocorticoids is associated with development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacologic interventions to these pathologies.
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