Robert J. Lefkowitz And Brian K. Kobilka Win 2012 Nobel Prize In Chemistry

Robert J. Lefkowitz, 69, and Brian K. Kobilka, 57, will take home this year’s Nobel Prize in Chemistry for unraveling the molecular workings of G-protein-coupled receptors (GPCRs). The receptors are a family of proteins that transmit critical biological messages for functions such as vision, smell, taste, and neurotransmission, and they are targets for myriad drugs.

GPCRs “are crucially positioned to regulate almost every known physiological process in humans,” Lefkowitz, a Howard Hughes Medical Institute investigator based at Duke University Medical Center, said by phone at an Oct. 10 press conference. For decades, researchers knew that hormones outside cells led to changes inside cells. But the exact nature of this chemical signaling was a mystery. Lefkowitz first traced the receptors responsible for this signaling with radioactive blocking or activating agents.

Kobilka, now at Stanford University School of Medicine, was a postdoc in Lefkowitz’ lab in the 1980s when the lab was hunting for the gene encoding the β adrenergic receptor. When Kobilka finally isolated the gene, he realized the receptor comprised seven helices, just like rhodopsin, which resides in the retina and responds to light. Kobilka and Lefkowitz surmised that a large family of seven-helix receptors—the GPCRs—must exist.

“There’s no question this work deserves the chemistry prize,” says University of Wisconsin, Madison, chemist Samuel H. Gellman, who has collaborated with Kobilka. “These proteins are vitally important molecules,” he explains, and although the work may sound heavily biological, the duo “did the kinds of things any chemist who wanted to understand a molecule would do.”

GPCRs are targets for as many as 50% of medications on the market, but many of those drugs, such as beta-blockers, date to long before the prizewinning discoveries. “Chemists made early GPCR drugs by just making molecules related to natural hormones or neurotransmitters,” says Fiona H. Marshall, chief scientific officer of Heptares Therapeutics, a firm that specializes in GPCR drug discovery. Lefkowitz and Kobilka’s work allows medicinal chemists to better understand the proteins they are targeting as they go about designing new drugs, she adds.

Both winners have founded firms to aid the drug discovery effort—Lefkowitz’ Trevena focuses on avoiding drug side effects, and Kobilka’s ConfometRx helps companies determine GPCR structures. “I hope my discovery leads to better and less-expensive drugs for patients,” Kobilka said in a statement.

Although the Nobel Committee pointed to Kobilka’s more recent research achievements, including the first X-ray crystal structure of a GPCR bound to its signaling partner, “this Nobel Prize is not just about the GPCR structure,” Marshall says. “That was the icing on the cake at the end.”

Lefkowitz and Kobilka will split the $1.2 million prize, which Lefkowitz said he didn’t anticipate. “I can assure you I did not go to sleep ... waiting for this call.” On the day of the announcement, Lefkowitz had initially planned to get a haircut.

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ACS President Bassam Z. Shakhashiri, Ph.D., comments on today’s Nobel Prize in Chemistry.