Their research, conducted over four decades, has elucidated the workings of “G-protein-coupled receptors,” a family with about 1,000 varieties that are involved in everything from sight and smell to the regulation of pain and heart rate.
More than one-third of all drugs on the market — including beta blockers, antihistamines and opioid painkillers — operate through G-protein-coupled receptors. Work in the past few years that reveals receptor structure in atomic detail may eventually lead to drugs with more precise action and fewer side effects.
In making the announcement, the Royal Swedish Academy of Sciences said the pair had made “groundbreaking discoveries” and called Kobilka’s success last year in crystallizing a receptor at the moment it is being activated a “molecular masterpiece.” The two will share about $1.2 million.
With its insights both crucial to understanding cell biology and highly useful to clinical medicine, a Nobel for this field had long been predicted.
“This could have been a prize in physiology or medicine, but it’s the chemical nature of the changes [driven by the receptors] that is being recognized here,” said Bassam Shakhashiri, president of the American Chemical Society and a professor at the University of Wisconsin.
At a news conference, Lefkowitz said he and Kobilka “couldn’t be more different.” Lefkowitz is a voluble, Bronx-accented New Yorker; Kobilka is a taciturn, small-town Minnesotan. Lefkowitz said the two had talked by Skype earlier in the day, and Lefkowitz had said Kobilka’s recent work is “maybe what pushed this over the line” into prize-winning territory. Kobilka demurred and said Lefkowitz’s work is what made his achievement possible.
“What little was said was really very moving,” he told the news conference, his voice catching.
Lefkowitz’s research has been supported by the Howard Hughes Medical Institute, based in Chevy Chase, since 1976 — longer than any other of the institute’s fellows, he said.
G-protein-coupled receptors are embedded in the thin membrane of cells. The “receptor” part is outside the cell, in contact with the environment. The“G protein” is inside the cell, in contact with the molecular machinery that does the cell’s work. There are seven ribbon-like strands of the protein that go back and forth through the membrane, stitching it in tightly.
The entire apparatus is a way for a cell to get information from the environment while still keeping itself intact and protected. It is such a successful piece of engineering that natural selection has tweaked and modified it for all kinds of purposes.
“I think that these proteins evolved to be very effective at detecting small things on the outside of the cell and activating big things inside the cell,” Kobilka told reporters in a conference call. “Once that problem was solved, we used the same method over and over again.”
The first receptor Lefkowitz identified and isolated was the “beta-2 adrenergic receptor,” which is the one that responds to adrenaline and is the target of asthma drugs such as albuterol. Lefkowitz said he picked it because there were many pharmacological tools with which to study its properties and, indirectly, its structure.
Kobilka, who like Lefkowitz trained to be a cardiologist, came to work in Lefkowitz’s lab at Duke in 1984. He helped determine the beta-2 adrenergic receptor’s amino acid sequence, which revealed that it was extremely similar to rhodopsin, which detects light in the retina. The function of those two proteins couldn’t be more different — and that was the first sign that G-protein-coupled receptors might be a large family with diverse functions.
Research since then has shown that G-protein-coupled receptors are involved in the detection of odor, the regulation of mood, the triggering of inflammation, the control of blood pressure.
Kobilka’s work led to the cloning of the gene for the adrenergic receptor, and eventually the genes for many others.
After moving to Stanford, Kobilka embarked on a 20-year-quest to isolate enough copies of various receptors to crystallize them into solid form, at which point their atomic structure could be studied by X-ray diffraction.
Getting simple compounds such as salt to form crystals is easy; getting complex proteins composed of thousands of atoms is almost impossible. Kobilka and his colleagues, however, have succeeded for an adrenergic and an opiate receptor. The detail afforded might allow medicinal chemists to design molecules that fit precisely into the “active site” of a receptor.
“I hope what we do will ultimately help to develop safer and more effective drugs in a more cost-effective way,” Kobilka said.