In this weekly seminar series, Scott Prosser, professor in the Department of Chemistry, University of Toronto, ON, Canada, will be giving a one-hour talk titled:
Understanding Receptor Pharmacology – NMR-Inspired Studies of GPCR Activation and Connections
ABSTRACT The G Protein-Coupled Receptor (GPCR) superfamily consists of over 830 distinct 7-transmembrane proteins, governing sensory and neuronal signaling, cell homeostasis, and immune response; 1/3 of all approved pharmaceuticals target GPCRs. Over 360 of these receptors are endo-GPCRs (other than olfactory, taste, and visual) and are thus potential drug targets. While functionally diverse, many GPCRs have common modes of activation. For example, the rhodopsin (class A) family, encompassing ~700 GPCRs, possesses a common network of “microswitches” that extend from the ligand binding pocket to the G protein binding interface. These microswitches respond cooperatively to agonists and dictate pharmacological response. The adenosine A2A receptor (A2AR) is a prototypical class A GPCR found in the cardiovascular, immune, respiratory, renal and central nervous systems. A2AR activation by endogenous adenosine mediates sleep, angiogenesis, and immune suppression, while specific agonists and antagonists have been clinically tested to treat inflammation, cancer, pain, and neurodegenerative diseases. Via mutagenesis, biophysical studies, and Nuclear Magnetic Resonance spectroscopy (NMR), we study A2AR conformational dynamics in response to drugs, to understand the role of microswitches in GPCR signalling – addressing questions of energetics, efficacy, biased signaling, allostery via cations and membrane adjuvants, and cooperative dynamics in the associated G protein. Some of our recent 19F NMR results on A2AR and its cognate G protein, Gs, will be presented, with a view towards new methodologies that may extend the reach of bio-NMR.
This seminar will be presented in the ASRC Auditorium and broadcast via Zoom, with snacks and refreshments to start at 11:30am in the cafe.
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