[HTML][HTML] Structural basis of AMPK regulation by adenine nucleotides and glycogen
Cell research, 2015•nature.com
AMP-activated protein kinase (AMPK) is a central cellular energy sensor and regulator of
energy homeostasis, and a promising drug target for the treatment of diabetes, obesity, and
cancer. Here we present low-resolution crystal structures of the human α1β2γ1 holo-AMPK
complex bound to its allosteric modulators AMP and the glycogen-mimic cyclodextrin, both
in the phosphorylated (4.05 Å) and non-phosphorylated (4.60 Å) state. In addition, we have
solved a 2.95 Å structure of the human kinase domain (KD) bound to the adjacent …
energy homeostasis, and a promising drug target for the treatment of diabetes, obesity, and
cancer. Here we present low-resolution crystal structures of the human α1β2γ1 holo-AMPK
complex bound to its allosteric modulators AMP and the glycogen-mimic cyclodextrin, both
in the phosphorylated (4.05 Å) and non-phosphorylated (4.60 Å) state. In addition, we have
solved a 2.95 Å structure of the human kinase domain (KD) bound to the adjacent …
Abstract
AMP-activated protein kinase (AMPK) is a central cellular energy sensor and regulator of energy homeostasis, and a promising drug target for the treatment of diabetes, obesity, and cancer. Here we present low-resolution crystal structures of the human α1β2γ1 holo-AMPK complex bound to its allosteric modulators AMP and the glycogen-mimic cyclodextrin, both in the phosphorylated (4.05 Å) and non-phosphorylated (4.60 Å) state. In addition, we have solved a 2.95 Å structure of the human kinase domain (KD) bound to the adjacent autoinhibitory domain (AID) and have performed extensive biochemical and mutational studies. Together, these studies illustrate an underlying mechanism of allosteric AMPK modulation by AMP and glycogen, whose binding changes the equilibria between alternate AID (AMP) and carbohydrate-binding module (glycogen) interactions.
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