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Dr. GPCR Podcast

Dr. Roger Sunahara

About Dr. Roger Sunahara

Professor Sunahara received his graduate training with Dr. Philip Seeman in the Department of Pharmacology at the University of Toronto. He later joined the laboratory of eminent biochemical pharmacologist, Dr. Alfred G. Gilman, at the University of Texas Southwestern Medical School as a post-doctoral fellow. His training has provided a strong foundation and appreciation for the applications of pharmacology, biochemistry and structural biology to delineate mechanisms of action. Professor Sunahara started his independent research career in the Department of Pharmacology at the University of Michigan Medical School, where he climbed the academic ladder. In 2015 Professor Sunahara moved his laboratory to the Department of Pharmacology at the University of California in San Diego. His main area of research focuses on the structural and pharmacological bases for hormone-mediated activation of G proteins by G protein-coupled receptors (GPCRs).

The Sunahara lab utilizes biochemical, biophysical and pharmacological methodologies to study GPCR-G protein interactions. These approaches were invaluable to resolve the crystal structure of the beta2-adrenergic receptor (beta2AR)-G protein complex, team effort with long time collaborator Brian Kobilka . The structure was first snapshot of the agonist- and G protein-bound GPCR, providing valuable models for agonist-mediated activation of G proteins. We continue to utilize these data to better understand the basis for receptor-G protein specificity and agonist efficacy. Our mission is to understand the mechanism and structural bases for ligand binding and efficacy to help optimize the design and engineering of more efficacious therapeutics. This is an important perspective in the pursuit of receptor subtype-specific ligands, a major aspect to achieve safer, on-target therapeutics. One example of our recent work surrounds a structure-based effort to develop ligands that specifically target the beta2AR above all other adrenergic receptor isoforms. Our goal is to develop safer beta2AR-selective ligands for the treatment of asthma and acute rescue therapy for anaphylaxis. We also study non-canonical sites, those outside of the native hormone, or orthosteric, binding sites. We have identified several GPCR ligands that allosterically modulate orthosteric ligand binding and target sites that are often located in regions that display higher sequence variability among receptor subtypes. Again, our intention is to target specific receptor subtypes.

The structural work on the GPCR-G protein complexes have also revealed some unprecedented conformational changes in G protein structure. Some of these changes are associated with G protein activation while the functional consequences of other structural changes remain elusive. More recently we have have been heavily engaged in studies to address the functional role of these dramatic conformational changes and the relationship to disease. Some of these studies resolved a major question regarding the signaling differences in G protein splice forms, specifically the short and long forms of the stimulatory G protein, Galpha-s(s) and Galpha-s(l), respectively. We demonstrated that Galpha-s(l), but not Galpha-s(s), regulates extracellularly regulated kinases (ERK), and that this long isoform is tied to a devastating blood disorder, myelodysplastic syndrome (MDS). We speculate that these aberrations in Galpha-s(l), specifically, may be involved in other pathologies such as cancer.

The Sunahara lab has also been developing protein-based therapeutics using structure-guided design and validation. A notable therapeutic is an enzyme that hydrolyzes cocaine. Through structural and computational approaches the Sunahara lab and collaborators developed a thermostable form of the enzyme that has recently progressed through Phase II clinical trials as an antidote for cocaine overdose. The laboratory continues to engineer the enzyme to optimize its potential as a treatment for cocaine abuse, a debilitating disease that would require long-term and sustained therapeutic actions.

Dr. Roger Sunahara on the web

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