Head of fruit fly in cross section

Steve Gamblin group project:

AMP-activated protein kinase

AMP-activated protein kinase (AMPK) regulates cellular metabolism in response to the availability of energy and is therefore a target for type II diabetes treatment. It senses changes in the ratio of AMP/ATP by binding both species in a competitive manner. Thus, increases in the concentration of AMP activate AMPK resulting in the phosphorylation and differential regulation of a series of downstream targets that control anabolic and catabolic pathways.

We have solved high-resolution crystal structures of the regulatory fragment of mammalian AMPK in complexes with AMP and ATP (Figure 2). Structural and solution studies reveal that two sites on the γ domain bind either AMP or Mg ATP, whereas a third site contains a tightly bound AMP that does not exchange. The phosphate groups of AMP/ATP lie in a groove on the surface of the γ domain, which is lined with basic residues, many of which are associated with disease-causing mutations. Our binding studies indicate that under physiological conditions AMPK mainly exists in its inactive form in complex with Mg ATP, which is much more abundant than AMP. Further studies are ongoing to fully understand the molecular basis of cellular energy regulation of AMP-activated protein kinase.

Figure 2

Figure 2

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Structure of mammalian AMP-activated protein kinase with AMP molecules bound.

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