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Some 700 approved therapies in the United States — roughly a third of all drugs on the market — target G-protein-coupled receptors (GPCRs). Now advances in high-throughput and structure-based screening are sparking a second golden age of GPCR-based drug discovery.
Encapsulated in cell surface membranes, GPCRs trigger metabolic changes in response to binding by hormones, neurotransmitters and drugs. Nearly all physiological processes depend on these receptors, but when Robert Lefkowitz first joined the faculty at Duke University in 1973, their existence was still in doubt. For many scientists, “GPCRs were a vague concept with no basis in physical reality,” Lefkowitz says. Eventually, Lefkowitz proved the doubters wrong. His success leading the first team to ever purify and clone a GPCR — the β2−adrenergic receptor — produced a Nobel Prize that the Duke professor shared in 2012 with Brian Kobilka, now at Stanford, who solved the receptor’s crystal structure.