Exploring the Landscape of Membrane Receptors
Ever wonder how caffeine works so marvelously to give you that extra boost you need the night before your final exam?
The class of receptors responsible for regulating neuronal function are part of the focus of a recent study out of the lab of Professor Scott Prosser in the Department of Chemical & Physical Sciences at U of T Mississauga. Their paper, “Activation of the A2A adenosine G-protein-coupled receptor by conformational selection,” appears in the latest edition of the prestigious international science journal, Nature.
There is a great deal of interest in understanding this broad class of cell signaling receptors called GPCRs (G-Protein-Coupled Receptors), which are responsible for basic processes such as vision, taste, smell, chemical signaling in the brain, cell homeostasis, and immune defense. 30-40% of current pharmaceuticals target these membrane receptors, which essentially serve as gate-keepers for cell signaling. “With our latest findings, we can begin to design the next generation of GPCR drugs whose precise pharmacological effects act against specific intermediates,” says Prosser.
He explains that GPCRs are often likened as molecular switches, which are blocked or turned on or off by drugs. Since 2007, X-ray crystallography has revealed a wealth of high-resolution structures of these “switches.” However, Prosser's NMR studies allow them to assess a broad conformational landscape in these receptors, and in so doing, understand the molecular underpinnings of many pharmacological effects.
Prosser and his lab began this line of inquiry in collaboration with Professor Wayne Hubbell from UCLA and Nobel Laureate, Brian Kobilka at Stanford, which resulted in several key papers, including an article published in May 2015 in the journal, Cell.
More recently, work in Prosser’s lab, led by postdoctoral scientist, Libin Ye, resulted in the current breakthrough. “This paper also represents a collaboration with a noted crystallographer, Oliver Ernst, in the Biochemistry Department at U of T,” says Prosser.
“This work delves further into the conformational landscape of these neuronal receptors, which are some of the most important drug targets in inflammation, cancer, sickle cell disease, diabetes, and brain disorders such as Parkinson’s disease.”
And yes, in case you were still wondering, caffeine does indeed bind to this receptor, keeping the normal sleep-inducing molecule (adenosine) out of the ligand binding pocket, giving you those extra few hours to prep for your exam in the morning.