The winners, Dr. Robert J. Lefkowitz, 69, a professor at Duke University Medical Center in Durham, N.C., and a Howard Hughes Medical Institute researcher, and Dr. Brian K. Kobilka, 57, a professor at the Stanford University School of Medicine in California, will split eight million Swedish kronor, or about $1.2 million.
Dr. Lefkowitz spoke by telephone during the news conference Wednesday at the Royal Swedish Academy of Sciences in Stockholm, which awards the Nobels, and said he did not hear the ringing of the early morning phone call to tell him that he had won.
“I wear earplugs when I sleep, and so my wife gave me an elbow,” he said. “And there it was, a total shock and surprise, as many before me have experienced.”
It also changed his plans for the day.
“I was going to get a haircut,” Dr. Lefkowitz said, “which if you could see me, you would see is quite a necessity, but I’m afraid that’ll probably have to be postponed.”
Dr. Lefkowitz and Dr. Kobilka filled in a major gap in the understanding how cells work and respond to outside signals.
“It’s a great tribute to human ingenuity and helping us learn intricate details of what goes on in our bodies,” said Bassam Shakhashiri, president of the American Chemical Society.
Scientists already knew, for example, that stress hormones like adrenaline trigger the body’s fight-or-flight reflex — focusing vision, quickening breathing, diverting blood away from less urgent body systems like the digestive tract — but adrenaline never enters the cells.
“A receptor was correctly assumed to be involved,” said Sven Lidin, a member of the Nobel Prize committee for chemistry during a news conference on Wednesday, “but the nature of this receptor and how it reacted remained a mystery for a long time.”
Dr. Lefkowitz said that although the notion of cell receptors went back more than a century, “when I kind of started my work in the area in the early ’70s, there was still a lot of skepticism as to whether there really was such a thing.” By attaching radioactive iodine to a hormone, Dr. Lefkowitz was able to track the movement of the hormone and explore the behavior of these receptors. Over the years, he was able to pull out the receptor proteins and show they were specific molecules.
In the 1980s, his group, which included Dr. Kobilka as a postdoctoral researcher, searched for and found the gene that produced one of these protein receptors. The genetic blueprint indicated that the shape of the protein included long spirals that wove through the cell membrane seven times. Meanwhile, other researchers had discovered a class of proteins, called G proteins, inside the cell that, when activated, set off a Rube Goldberg cascade of molecular machinery.
The receptor was the last missing piece. “If you have something like adrenaline, it sticks in there, turns the key, changes the shape of the receptor, and now the receptor, having changed shape, is able to tickle the G protein,” Dr. Lefkowitz said.
There was a “eureka moment,” Dr. Lefkowitz said, when he realized that his receptor was the same as another receptor that had been found in another part of the body — the light receptor rhodopsin in the retina. “We said, ‘Well, wait a moment, maybe anything which couples to a G protein looks like this,’ ” he said.
Within a year, they were able to decode the genetic blueprints for several other similar receptors, and they were right.
About 1,000 of these receptors, known as G protein-coupled receptors, are now known, residing on the surface of cells and reacting to a host of hormones and neurotransmitters.
Dr. Lidin of the Royal Swedish Academy said that it turned out that half of all drugs target such receptors.
Dr. Kobilka, who moved to Stanford, then set out to determine the three-dimensional structure of the receptor, which requires building a crystal out of the proteins and then deducing the structure by bouncing X-rays off it. Membrane proteins are notoriously difficult to pack into crystals. Last year, he and his research group were able to get an image of a receptor at the moment it was transferring a signal from the outside of the cell to a protein on the inside.
Knowledge about the shapes of different receptors could refine drug design. Many drug molecules attach to cells not only at the intended target but also to other receptors, causing side effects.
“We hope by knowing the three-dimensional structure we might be able to develop more selective drugs and more effective drugs,” Dr. Kobilka said.
Dr. Kobilka received his good-news phone call at 2:30 in the morning California time. “When you have a number of people with credible Swedish accents congratulating you, you feel it’s probably not a joke someone is playing on you,” he said.
