Part of the work of the Shapiro lab relates to the protein chemistry and structural biology of proteins involved in energy homeostasis. This work is now focused on understanding the structure and mechanism of the AMP-activated protein kinase (AMPK). AMPK coordinates metabolic function with energy availability by responding to changes in intracellular ATP (adenosine triphosphate) and AMP concentrations. We have determined numerous crystal structures of the regulatory “core” of AMPK in complex with its regulatory ligands (1,2). These structures show that ATP and AMP bind competitively to a single site in the gamma subunit, with their respective phosphate groups positioned near function-impairing mutants.

Figure: < st1:place style=font-family: Times New Roman; w:st=on>< st1:city w:st=on>Crystal structure of S. pombe AMPK regulatory domain structure.  Each of the three subunits is indicated, and the positions of adenine nucleotide binding sites are shown. The lower panel gives a schematic diagram of the corresponding sequence regions using the same color scheme.

The structures determined so far by us are for the AMPK homolog from the fission yeast S. pombe. However, the regulation of this enzyme has not been investigated in detail, making solution of the human structure a critical goal. Our current work is focused on determining structures for the heterotrimeric human AMPK isotypes. These studies could in principle point the way toward the design of therapeutic compounds targeting this important regulatory enzyme.

Publications

Science
2007;315:1726-1729
Crystal Structures of the Adenylate Sensor from Fission Yeast AMP-Activated Protein Kinase.
Townley R, Shapiro L
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