Longevity & AgingCrystal Structure Reveals How Potent AMPK Inhibitor BAY-3827 Silences Energy Sensor
AMPK is a master energy sensor implicated in metabolism, aging, and disease. While AMPK activators are well-studied, high-quality inhibitors have been scarce. Researchers solved a 2.5-Å crystal structure of the AMPK kinase domain bound to BAY-3827, revealing a unique disulfide bridge between two cysteine residues that locks the enzyme in an inactive conformation by disrupting the regulatory spine. In hepatocytes, BAY-3827 blocked AMPK activator MK-8722-induced phosphorylation of ACC1 and suppressed lipogenesis. Transcriptome analysis showed BAY-3827 down-regulated roughly 30% of AMPK-dependent genes activated by MK-8722, establishing both the utility and the limitations of this tool compound for dissecting AMPK biology.
