1. MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
2. MRC Clinical Sciences Centre, Hammersmith Hospital Campus, Imperial College, DuCane Road, London W12 0NN, UK

Correspondence to: Stephen R. Martin¹David Carling²Steven J. Gamblin¹ Correspondence and requests for materials should be addressed to S.R.M. (Email: smartin@nimr.mrc.ac.uk), D.C. (Email: david.carling@csc.mrc.ac.uk) or S.J.G. (Email: sgambli@nimr.mrc.ac.uk).

Abstract

AMP-activated protein kinase (AMPK) regulates cellular metabolism in response to the availability of energy and is therefore a target for type II diabetes treatment¹. It senses changes in the ratio of AMP/ATP by binding both species in a competitive manner². 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^{1, 2}. We report here the crystal structure of the regulatory fragment of mammalian AMPK in complexes with AMP and ATP. The phosphate groups of AMP/ATP lie in a groove on the surface of the domain, which is lined with basic residues, many of which are associated with disease-causing mutations. Structural and solution studies reveal that two sites on the domain bind either AMP or MgATP, whereas a third site contains a tightly bound AMP that does not exchange. Our binding studies indicate that under physiological conditions AMPK mainly exists in its inactive form in complex with MgATP, which is much more abundant than AMP. Our modelling studies suggest how changes in the concentration of AMP ([AMP]) enhance AMPK activity levels. The structure also suggests a mechanism for propagating AMP/ATP signalling whereby a phosphorylated residue from the and/or subunits binds to the subunit in the presence of AMP but not when ATP is bound.

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