Researching the Receptors

At this year’s Smithies Nobel Symposium lecture, Stanford’s Brian Kobilka spoke on the importance of GPCRs in drug development.

Researching the Receptors click to enlarge Brian Kobilka, MD (photo by Brian Strickland)
Researching the Receptors click to enlarge (Photo by Brian Strickland)

You take a drug. It does what it’s supposed to do. And it does some other things you wish it didn’t, such as produce drastic side effects. Nearly half of all drugs hit G protein-coupled receptors (GCPRs) in the surface membranes of cells. One such drug is morphine. Another is oxycodone. The main side effect of these drugs, aside from addiction, is that they affect receptors in such a way that they can cause a person to stop breathing.

Brian Kobilka, MD, the 2016 lecturer during the annual Oliver Smithies Nobel Symposium at UNC, is part of an international team of scientists – including a few at UNC – trying to create a “better morphine,” one that doesn’t have the addictive and non-breathing characteristics of opioids, the abuse of which has become an epidemic in the United States.

But to build this better kind of opioid, Kobilka and others had to explore the basic underlying biology of these receptors. While working in the lab of Robert Lefkowitz, MD, at Duke, Kobilka cloned the gene that codes for a variety of adrenergic receptors, and his analysis of these initial genetic sequences revealed a common transmembrane architecture similar to that of rhodopsin, a G protein-coupled receptor specialized for light detection. This opened up a new research avenue, and Kobilka began exploring these receptors at the molecular level.

In 1989, Kobilka, joined the faculty at Stanford, where his lab focused on understanding the structure GPCRs and how they are activated. In 2007, he made a major breakthrough when his lab published the structure of the Beta-2 Adrenergic Receptor (B-2AR) in an inactive state bound to an antagonist ligand – a compound that blocks a receptor to inhibit a biological response. In 2011, his lab determined the structure of the agonist-bound B-2AR as it interacts with a G protein – a structure that fellow scientists have called “a molecular masterpiece.”

This work in total tells the story of GCPR activation and opened the door to structure-based drug design, which could undergird the development of new drugs that hit intended biological targets without causing dramatic, negative side effects.

During his lecture, he ended on a collaborative note, highlighting the latest research involving UNC’s Bryan L. Roth, MD, PhD; Brian Shoichet, PhD, at UC-San Francisco; and Peter Gmeiner, PhD, at Friedrich-Alexander University Erlangen-Nürnberg in Germany.

KOBILKA AND SMITHIES
Brian Kobilka and Oliver Smithies talk science at the 2016 Oliver Smithies Nobel Symposium this week at the UNC School of Medicine.

These researchers used the newly deciphered atomic structure of the brain’s “morphine receptor” to custom-engineer a new drug candidate that blocked pain as effectively as morphine in mouse experiments but did not share the potentially deadly side effects typical of opioid drugs, including morphine and oxycodone. In particular, the new drug did not interfere with breathing – the main cause of death in overdoses of prescription painkillers as well as street narcotics like heroin – or cause constipation, another common and sometimes severe opioid side effect. In lab tests, the new drug also appeared to side-step the brain’s dopamine-driven addiction circuitry and did not cause drug-seeking behavior in mice, though more studies are needed to confirm this observation.

In 2012, Kobilka was awarded the Nobel Prize in Chemistry with Lefkowitz. Currently, Kobilka is the Helene Irwin Fagan Chair in Cardiology at Stanford. 

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