In March, researchers visualized opioid receptors for the first time, when two independent groups reported X-ray crystal structures of two family members, the mu (μ) and kappa (κ) receptors (see PRF related news story). Now, the same teams are rolling out structures of the two remaining opioid receptors, each bound to an antagonist ligand. Brian Kobilka at Stanford University School of Medicine in California, US; Sébastien Granier at Stanford and INSERM, Montpellier, France; and colleagues solve a structure of the third classical opioid receptor, delta (δ), and Raymond Stevens at The Scripps Research Institute in La Jolla, California, US, and coworkers report a structure of an idiosyncratic member of the family, the nociceptin/orphanin FQ (N/OFQ or NOP) receptor (also known as opioid receptor like-1, ORL-1). The new structures (along with the original two, previously published online) appear in the May 17 issue of Nature.
The studies “provide the first direct evidence for the binding mode of opioids to their receptors,” write Marta Filizola and Lakshmi Devi, Mount Sinai School of Medicine, New York, US, in an accompanying News and Views. “This information will be invaluable for research aimed at finding opioid drugs that lack…adverse side effects.”
The structures show that all four opioid receptors contain seven membrane-crossing helices that are characteristic of G protein-coupled receptors, and which form a large ligand-binding pocket open to the extracellular space. Comparison of the structures reveals that ligand moieties that determine efficacy bind a conserved region at the base of the pocket, while other moieties that confer selectivity recognize variable regions higher in the pocket. Knowledge of these features should aid the search for drugs with both improved efficacy and specificity.
The current structures, however, are only the first step towards reaching that goal. All four depict inactive receptor conformations, whereas pain-relieving opioid drugs activate opioid receptors. Structures of the receptors in complex with different agonists, and with different signaling proteins, may aid the design of drugs that produce analgesia without the addiction and other side effects that plague the existing opioid armamentarium.
Image credit: From Filizola and Devi, 2012. Reprinted by permission from Macmillan Publishers Ltd: Nature 485: 314-316, copyright 2012.
Comments
Michael Bruchas, Washington University in St. Louis
This is a fantastic follow-up
This is a fantastic follow-up to the prior 2 papers (Mu and Kappa) just published in Nature. Having all 4 opioid receptors crystalized is a big step forward. Like others, I'm hopeful that follow-up studies will reveal the agonist bound state of the receptor, and potentially down the road structures for the receptors when they complex with other proteins including other receptor types. I'm particularly excited about the structure of ORL1 because the receptor is the least examined of the 4 receptor types in the opioid community, yet we now have a solid stepping stone to work from as we examine how this receptor works and potentially interacts with other proteins and ligands.
I think there is now an opportunity with these crystal structures being solved to take a look at these receptors in new ways. I'm hopeful that combined efforts of receptor pharmacologists and medicinal chemists can produce some new compounds for testing in vitro and in vivo.