Structural basis of AMPK regulation by adenine nucleotides and glycogen

Cell Res. 2015 Jan;25(1):50-66. doi: 10.1038/cr.2014.150. Epub 2014 Nov 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AMP-Activated Protein Kinases / chemistry*
  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Monophosphate / metabolism*
  • Adenosine Triphosphate / metabolism
  • Allosteric Regulation
  • Crystallography, X-Ray
  • Cyclodextrins / metabolism
  • Glycogen / metabolism*
  • Humans
  • Models, Molecular
  • Phosphorylation
  • Protein Conformation
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism


  • Cyclodextrins
  • Protein Subunits
  • Adenosine Monophosphate
  • Adenosine Triphosphate
  • Glycogen
  • AMP-Activated Protein Kinases