Scripps Florida scientists create 'fingerprints' for major drug development targets
For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have created detailed "fingerprints" of a class of surface receptors that have proven highly useful for drug development.
These detailed "fingerprints" show the surprising complexity of how these receptors activate their binding partners to produce a wide range of signaling actions.
The study focuses on interactions of G protein-coupled receptors (GPCRs) with their signaling mediators known as G proteins. GPCRs--currently accounting for about 40 percent of all prescription pharmaceuticals on the market--play key roles in many physiological functions because they transmit signals from outside the cell to the interior. When an outside substance binds to a GPCR, it activates a G protein inside the cell to release components and create a specific cellular response.
"Until now, it was generally believed that GPCRs are very selective, only activating few G proteins they were designed to work with," said TSRI Associate Professor Kirill Martemyanov, who led the study. "It turns out the reality is much more complex."
Ikuo Masuho, a senior research associate in the Martemyanov lab, added, "Our imaging technology opens a unique avenue of developing drugs that would precisely control complex GPCR-G protein coupling, maximizing therapeutic potency by activating G proteins that contribute to therapeutic efficacy while inhibiting other G proteins that cause adverse side effects."
The study found that individual GPCRs engage multiple G proteins with varying efficacy and rates, much like a dance where the most desirable partner, the GPCR, is surrounded by 14 suitors all vying for attention. The results, as in any dance, depend on which G proteins bind to the receptor--and for how long. The same receptor changes G protein partners--and the signaling outcome--depending on the action of the signal received from outside of the cell.
This finding was made possible by novel imaging technology used by the Martemyanov lab to monitor G protein activation in live cells. Using a pair of light-emitting proteins, one attached to the G protein, the other attached to what's known as a reporter molecule, Martemyanov and his colleagues were able to measure simultaneously both the signal and activation rates of most G proteins present in the body.
"Our approach looks at 14 different types of G proteins at once--and we only have 16 in our bodies," he said. "This is as close as it can get to what is actually happening in real time."
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