Structures of AMP-activated protein kinase bound to novel pharmacological activators in phosphorylated, non-phosphorylated, and nucleotide-free states.

ABSTRACT: AMP-activated protein kinase (AMPK) is an attractive therapeutic target for managing metabolic diseases. A class of pharmacological activators, including Merck 991, binds the AMPK ADaM site, which forms the interaction surface between the kinase domain (KD) of the α-subunit and the carbohydrate-binding module (CBM) of the β-subunit. Here, we report the development of two new 991-derivative compounds, R734 and R739, which potently activate AMPK in a variety of cell types, including β₂-specific skeletal muscle cells. Surprisingly, we found that they have only minor effects on direct kinase activity of the recombinant α₁β₂γ₁ isoform yet robustly enhance protection against activation loop dephosphorylation. This mode of activation is reminiscent of t

SUBMITTER: Yan Y 

PROVIDER: S-EPMC6341387 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature