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.
Structural Insight into AMPK Regulation: ADP Comes into Play.
Jin X, Townley R, Shapiro L