A conserved mechanism of autoinhibition for the AMPK kinase domain: ATP-binding site and catalytic loop refolding as a means of regulation

Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Feb 1;66(Pt 2):143-51. doi: 10.1107/S1744309109052543. Epub 2010 Jan 27.


The AMP-activated protein kinase (AMPK) is a highly conserved trimeric protein complex that is responsible for energy homeostasis in eukaryotic cells. Here, a 1.9 A resolution crystal structure of the isolated kinase domain from the alpha2 subunit of human AMPK, the first from a multicellular organism, is presented. This human form adopts a catalytically inactive state with distorted ATP-binding and substrate-binding sites. The ATP site is affected by changes in the base of the activation loop, which has moved into an inhibited DFG-out conformation. The substrate-binding site is disturbed by changes within the AMPKalpha2 catalytic loop that further distort the enzyme from a catalytically active form. Similar structural rearrangements have been observed in a yeast AMPK homologue in response to the binding of its auto-inhibitory domain; restructuring of the kinase catalytic loop is therefore a conserved feature of the AMPK protein family and is likely to represent an inhibitory mechanism that is utilized during function.

MeSH terms

  • AMP-Activated Protein Kinases / chemistry*
  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Triphosphate / chemistry*
  • Adenosine Triphosphate / metabolism*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Biocatalysis*
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Folding*
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Sequence Alignment


  • Protein Subunits
  • Adenosine Triphosphate
  • AMP-Activated Protein Kinases