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Cell. 2018 Jan 11;172(1-2):55-67.e15. doi: 10.1016/j.cell.2017.12.011. Epub 2018 Jan 4.

Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.

Author information

1
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
2
Molecular Pharmacology Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
4
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
5
Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonweath University, Richmond, VA 23298, USA.
6
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
7
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA; School of Molecular Sciences, Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA; Institute of Natural Resources and Environmental Audits, Nanjing Audit University, Nanjing, China.
8
Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium; VIB-VUB Center for Structural Biology, VIB, 1050 Brussels, Belgium.
9
National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
10
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
11
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: dwacker@email.unc.edu.
12
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: bryan_roth@med.unc.edu.

Abstract

The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics.

KEYWORDS:

GPCR; active state; addiction; crystallography; morphinan; nanobody; opioid receptor; structure-function

PMID:
29307491
PMCID:
PMC5802374
[Available on 2019-01-11]
DOI:
10.1016/j.cell.2017.12.011

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