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Biological Chemistry

Opioid Receptor Gang Of Four

Two teams raced to publish the structures of four membrane proteins that control pain and pleasure signaling in the body

by Lauren K. Wolf
December 24, 2012 | APPEARED IN VOLUME 90, ISSUE 52

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Credit: Courtesy of Raymond Stevens/Scripps
In these cutaway views, inhibitors nestle deeply into the large, open binding pockets of the four opioid receptors structurally characterized this year; the nonclassical receptor nociceptin is at left, and the three classical receptors are at right.
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Credit: Courtesy of Raymond Stevens/Scripps
In these cutaway views, inhibitors nestle deeply into the large, open binding pockets of the four opioid receptors structurally characterized this year; the nonclassical receptor nociceptin is at left, and the three classical receptors are at right.

It’s been a big year for G-protein-coupled receptors (GPCRs). Not only did the protein family garner the Nobel Prize in Chemistry (see above), but four of its members stepped into the spotlight. For the first time, researchers determined the X-ray crystal structures of opioid receptors, which are membrane proteins that mediate pain and pleasure in the body. In March, a friendly competition between two teams of scientists ended when Nature simultaneously published structures for the µ- and κ-opioid receptors (C&EN, March 26, page 11). One of the Nobel Laureates, Stanford University’s Brian K. Kobilka, teamed up with Stanford colleague Sébastien Granier and coworkers to crystalize a mouse µ-opioid receptor bound to the morphinelike inhibitor, β-funaltrexamine (DOI: 10.1038/nature10954). And a group led by Raymond C. Stevens of Scripps Research Institute characterized the human κ-receptor in a complex with an inhibitor called JDTic (DOI: 10.1038/nature10939). The two teams then raced to complete the gang of four opioid receptors, publishing structures for the remaining two in May (C&EN, May 21, page 32; Nature, DOI: 10.1038/nature11111 and 10.1038/​na​ture11085). The Stanford team unveiled the details of a mouse δ-opioid receptor, and the Scripps team presented the finer points of the human nociceptin (orphanin FQ) receptor; as before, both proteins were bound to inhibitors. The researchers are now comparing the structures and binding pockets of the three classical opioid receptors—µ, κ, and δ—and the nonclassical receptor nociceptin. Knowledge of how each receptor binds its inhibitor could eventually lead to the design of better painkillers and antidepressants.

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