Brian Kobilka, MD, who received the 2012 Nobel Prize in Chemistry for his studies of G protein-coupled receptors (GPCRs), shared his team’s progress in understanding receptor activation — and how that might guide drug development — at last week’s Flexner Discovery Lecture.
The lecture was the Earl W. Sutherland Lecture in honor of Vanderbilt’s second Nobel laureate. It was sponsored by the Department of Molecular Physiology and Biophysics.
Kobilka, professor of Molecular and Cellular Physiology at Stanford University, discussed data from a wide variety of studies probing receptor structure to explore the dynamic process of GPCR activation.
GPCRs transmit signals across the cell membrane to change the behavior of cells. More than 800 members of the GPCR family in the human genome conduct cellular responses to the majority of hormones and neurotransmitters and mediate the senses of sight, smell and taste.
They are the largest class of pharmaceutical targets; about 30 percent of small-molecule drugs target GPCRs.
GPCR structures include membrane-spanning domains that are represented by drawings that look something like a bundle of curled ribbons decorating a gift.
Kobilka showed how the “ribbons” — the membrane-spanning domains — move when hormones and drugs bind to a receptor, and how that movement changes the interaction of the receptor with the G protein that sends the signal along. Kobilka and his team are particularly interested in the specificity of receptor-G protein interactions.
They are also interested in using their results for drug discovery.
“Ultimately, if our crystal structures and our structural insights are to be useful, we have to find ways to develop and test for safer, more selective drugs,” Kobilka said.
He showed an example of such an approach. Muscarinic GPCRs of two different types — M3 and M2 — are present in the lung and in the heart, respectively. The drug tiotropium treats chronic obstructive pulmonary disease by blocking M3 receptors in the lung. But it also blocks M2 receptors in the heart equally well, causing side effects including increased heart rate and arrhythmias.
Using structural insights for the two receptors, Kobilka and his colleagues modified the drug chemistry to fit the binding pocket differently. They were able to generate a compound that was more selective for the M3 receptor, which they confirmed in animal studies.
They will continue to use this approach to improve the actions of other GPCR-targeted medications.
Kobilka holds the Helene Irwin Fagan Chair in Cardiology at Stanford and is a member of the National Academy of Sciences, the National Academy of Medicine and the American Academy of Arts and Sciences.
For a complete schedule of the Flexner Discovery Lecture series and archived video of previous lectures, go to mc.vanderbilt.edu/discoveryseries.
