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National Institute of General Medical Sciences (NIGMS) and National Cancer Institute (NCI) of the National Institutes of Health (NIH)

Structures of kappa-opioid and nociceptin/orphanin FQ receptors

Figure: Structure of the kappa-opioid receptor. The kappa-opioid receptor is surrounded by molecules of morphine and other opioid ligands (beta-funaltrexamine, JDTic, Banyu compound-24 and naltrindole), shown as orange spheres, on a background drawing of opium poppies and artistic smoke. (courtesy of TSRI).

Ray Stevens group (The Scripps Research Institute) and collaborators


The group of Ray Stevens at The Scripps Research Institute determined structures of two of the four types of opioid receptors, as featured in the journal, Nature, along with publications on the two other types of opioid receptors from the group of Brian Kobilka and collaborators. The Stevens group published structures for the kappa-opioid receptor (Wu et al. (2012)) and the nociceptin/orphanin FQ receptor (Thompson et al. (2012)) as part of the PSI sponsored GPCR Network Project. While opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, their ability to produce a strong sense of euphoria leads to rampant recreational use of prescription drugs and their more potent and deadly derivative, heroin. Opioid receptors are thus important drug targets, and although decades of focused medicinal chemistry efforts have yielded reasonably selective ligands for all four opioid receptors, there remains substantial interest in the development of subtype-selective agonists and antagonists. Using LCP-grown crystals and data collected with mini-beam and raster, these important results provide structural insights into the atomic details of molecular recognition and subtype selectivity of the opioid receptors and should catalyze the structure-based design of advanced agonists and antagonists with improved pharmacological profiles and enhanced therapeutic efficacies.



[1] Wu, H, Wacker, D, Mileni, M, Katritch, V, Han, GW, Vardy, E, Liu, W, Thompson, AA, Huang, XP, Carroll, FI, Mascarella, SW, Westkaemper, RB, Mosier, PD, Roth, BL, Cherezov, V, Stevens, RC. Structure of the human kappa-opioid receptor in complex with JDTic, Nature 485, 327-332 (2012)
[2] Thompson, AA, Liu, W, Chun, E, Katritch, V, Wu, H, Vardy, E, Huang, XP, Trapella, C, Guerrini, R, Calo, G, Roth, BL, Cherezov, V, Stevens, RC. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic, Nature 485, 395-399 (2012).

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