Issue Date: March 26, 2012
Opioid Receptors Revealed
A friendly competition to determine the structures of membrane proteins that mediate pain and pleasure has drawn to a close. Last week, Nature published two research teams’ X-ray crystal structures of the µ- and κ-opioid receptors, members of the G protein-coupled receptor (GPCR) family that bind drugs such as morphine and the hallucinogen salvinorin A (DOI: 10.1038/nature10954 and 10.1038/nature10939).
GPCRs are targets for approximately 40% of clinically approved drugs, so their structures are at the top of many drug companies’ wish lists. In particular, the µ- and κ-opioid receptor structures could aid in the design of new painkillers and antidepressants that have few side effects. No opioid receptor structures had previously been solved.
Neither team knew that the other had solved its opioid receptor structure until both attended a GPCR workshop held last December in Hawaii. After each group announced its results, “the race was on” to publish, says Bryan L. Roth, a member of the κ-opioid receptor team and a pharmacologist at the University of North Carolina, Chapel Hill.
Raymond C. Stevens of Scripps Research Institute led the κ receptor team, which determined the structure of the human κ receptor complexed with the inhibitor JDTic, a drug candidate for treating addiction.
Stevens’ team found that, compared with previously solved GPCR structures, the κ receptor has an exceptionally large binding pocket. On the basis of previous modeling and mutagenesis studies, Roth says, “it was never clear why κ could bind so many different types of compounds. Now it’s very clear.” The pocket fits many molecules, he explains, and their binding strength depends upon which of the pocket’s amino acid residues they interact with.
The µ receptor team, led by Brian K. Kobilka and Sébastien Granier of Stanford University’s School of Medicine, also found that its membrane protein has a big, exposed binding pocket. The researchers solved the structure of a mouse µ-opioid receptor bound to the inhibitor β-funaltrexamine, a morphinelike compound.
Both teams found that their receptors dimerized. Pairs of µ receptors have especially large surface areas, Kobilka says. It’s not clear at this point what the significance of this dimerization might be or whether it occurs in cell membranes, he adds, but “the structure will help design experiments to test the functional role of this interface.”
Although the two teams have yet to closely compare structural data, this is where the real excitement will be, says Christopher G. Tate, a structural biologist at MRC Laboratory of Molecular Biology, in England. “Comparing in minute detail how the two receptors bind their respective inhibitors,” he adds, “should help in making drugs that bind specifically to only one receptor in the opioid receptor family.”
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