Researchers at the Florida campus of The Scripps Research Institute (TSRI) report that they discovered a number of important features that explain what turns on a protein—AMPK—that is considered to be a master regulator of how the human body uses and stores energy. They believe that the new discoveries could help in the design and development of new therapeutics to treat metabolic disease such as diabetes and obesity, and maybe some forms of cancers.
The study (“Activation of AMP-Activated Protein Kinase Revealed by Hydrogen/Deuterium Exchange Mass Spectrometry”), led by Patrick R. Griffin, Ph.D., chair of the TSRI department of molecular therapeutics, is published online in Structure.
ATP stores what cells use for fuel. The balance between stored energy and energy consumption is in constant flux, so the ability to sense changes in those energy supplies is essential for survival, according to the scientists. When energy reserves run low, AMP-activated protein kinase (AMPK), which monitors cellular energy levels, stimulates the generation of ATP and increases those energy stores.
As a result, AMPK has become an attractive target for the treatment of metabolic diseases like diabetes and obesity. But the development of molecular activators of kinase has lagged behind inhibitors because while inhibition is straight forward, less is understood about the mechanism of hyperactivation of kinases.
“Other research has revealed compounds that activate AMPK,” said Dr. Griffin. “However, until our study no one has been able to confirm exactly where those compounds bind, nor how binding of these molecules leads to an increase in the activity of the kinase.”
In the new research, Dr. Griffin and his colleagues not only identified the subunit where binding took place, but were able to show that binding by a known AMPK activator fully activates the protein—specifically through biochemical communication with the other subunits, a process that allows AMPK to respond quickly to changes in the cellular energy levels.
“Results from [our] analysis clearly show that binding of AMP leads to conformational changes primarily in the gamma subunit of AMPK and subtle changes in the alpha and beta subunits,” wrote the investigators. “In contrast, A769662 [a synthetic small molecule regulator] causes profound conformational changes in the glycogen binding module of the beta subunit and in the kinase domain of the alpha subunit, suggesting that the molecular binding site of the latter resides between the alpha and beta subunits.”
Based on this work Dr. Griffin explained that other researchers can now model AMPK activators to see is they might be developed as potential drugs.
