Structural basis for compound C inhibition of the human AMP-activated protein kinase α2 subunit kinase domain

Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):480-7. doi: 10.1107/S0907444911010201. Epub 2011 Apr 14.


AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor to maintain energy balance at both the cellular and the whole-body levels and is therefore a potential target for drug design against metabolic syndrome, obesity and type 2 diabetes. Here, the crystal structure of the phosphorylated-state mimic T172D mutant kinase domain from the human AMPK α2 subunit is reported in the apo form and in complex with a selective inhibitor, compound C. The AMPK α2 kinase domain exhibits a typical bilobal kinase fold and exists as a monomer in the crystal. Like the wild-type apo form, the T172D mutant apo form adopts the autoinhibited structure of the `DFG-out' conformation, with the Phe residue of the DFG motif anchored within the putative ATP-binding pocket. Compound C binding dramatically alters the conformation of the activation loop, which adopts an intermediate conformation between DFG-out and DFG-in. This induced fit forms a compound-C binding pocket composed of the N-lobe, the C-lobe and the hinge of the kinase domain. The pocket partially overlaps with the putative ATP-binding pocket. These three-dimensional structures will be useful to guide drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors*
  • AMP-Activated Protein Kinases / chemistry*
  • AMP-Activated Protein Kinases / genetics
  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 2 / enzymology
  • Humans
  • Metabolic Syndrome / enzymology
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Obesity / enzymology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Sequence Alignment


  • Protein Kinase Inhibitors
  • Protein Subunits
  • AMP-Activated Protein Kinases

Associated data

  • PDB/2YZA
  • PDB/3AQV