UTM biochemist highlights amazing complexities of cell’s chemical gatekeepers

Scott Prosser
Thursday, July 28, 2016 - 11:23am
Elaine Smith

Good things seem to come in threes for Scott Prosser, a professor of biochemistry at U of T Mississauga.

A research paper about chemical gatekeepers that he authored appears in the July issue of Nature, following on the heels of two other recent papers published in Cell and Nature. His most recent work has two prominent co-authors: noted Nobel laureates, Brian Kobilka at Stanford University Medical School and Bob Lefkowitz at Duke University Medical School.

“These people are godfathers in the field of cell signalling and GPCRs (G protein coupled receptors),” says Prosser. “It’s a great privilege to be able to work with them and make a contribution to basic medical science through nuclear magnetic resonance (NMR).”

The research conducted by Prosser and his colleagues focuses specifically on GPCRs. If you’ve ever wondered how a photon is turned into a chemical signal for vision or how an odour triggers the sense of smell, look no further than GPCRs. These cell membrane receptors act as chemical gatekeepers in our bodies. Humans possess almost 1,000 different types of the G protein coupled receptors.

Prosser describes this research this way: If a tiny hormone or a chemical ligand knocks on the door of the GPCR gatekeeper, these visitors bind to a specific pocket on the outside of the cell and initiate a change to the receptor on the inside of the cell. These actions suddenly allow the GPCR to interact with a number of proteins in the cell interior, triggering a signaling cascade.

Drugs can also trigger these signalling reactions; many drugs are designed to compete for the special keyhole guarded by a particular GPCR. In fact, approximately one-third of all drugs on the market today target GPCRs.

Previously, scientists viewed GPCRs simply as switches that are turned on or off by drugs that knock at their gates. However, Prosser’s research highlights the amazing complexity of these receptors, which are actually remarkably pliable and dynamic molecules capable of binding to other receptors and to many intracellular partners, thus giving rise to a dizzying number of signalling responses of differing intensity.

Prosser and members of his group, Tae Hun Kim and Libin Ye, along with noted Canada Excellence Research Chair in Structural Neurobiology, Professor Oliver Ernst, and others used NMR to demonstrate the complexity of GPCRs.

“For the first time, we were able show the co-existence of multiple states of the receptor in living colour, along with being able to read out lifetimes of these states, and the influence of drugs on the entire landscape. Many of these results are laying the foundation for a molecular explanation to many pharmacological phenomena.

“Often GPCR drugs give rise to bizarre behavior in cells – weak response, promiscuity (multiple pathways), the nearly complete shutting down of signalling or synergistic effects in combination with other drugs. Finally, we have a basis with which to begin to explain these phenomena,” said Prosser, who anticipates publishing at least three more papers on the subject in the near future.

Indeed, the third time’s the charm.