ArticleCell2018
Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.
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Article in Cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 211 papers.
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211citing papers in PubMed
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Who cites it
211 citing papers in PubMed, 363 citations in OpenAlex.
- Atomic, structural and molecular insights into GPCR ligand binding and signalling.Nature reviews. Molecular cell biology · 2026Review
- Structural basis of opioid receptor activation by PCP and ketamine.Nature structural & molecular biology · 2026Article
- Structural dynamics of kappa opioid receptor interactions with β-arrestin 1.Nature communications · 2026Article
- Structural characterization of kappa-opioid receptor dimer in complex with two G proteins.Nature communications · 2026Article
- Molecular mechanisms for subtype selectivity of kinin receptors' antagonists.Nature communications · 2026Article
- Selective positive allosteric modulation of βNature communications · 2026Article
- Structural and dynamic studies uncover a distinct allosteric modulatory site at the µ-opioid receptor.Nature communications · 2026Article
- Identification of Subtype-Selective Binding Sites in the Opioid Receptor Family.Journal of chemical information and modeling · 2026Article
- Unraveling allosteric signaling of G protein-coupled receptors (GPCRs) by single-molecule fluorescence.Biophysical reviews · 2026Review
- Mechanistic Insights into G Protein-Biased κ-Opioid Receptor Signaling Using Dual-Charged Naltrexamine Amides.Journal of medicinal chemistry · 2026Article
- Opioid Receptors in Psychedelia: Indirect Serotonergic Modulation of Direct KOR Activation by Salvinorin A.Biomedicines · 2026Review
- Structure-based design of an opioid receptor modulator for enhanced morphine analgesia.Science advances · 2026Article
- An engineered nanobody inhibitor for molecular-to-circuit control of opioid receptor function.bioRxiv : the preprint server for biology · 2026Article
- Differential Effects of Sodium on Agonist-Induced Conformational Transitions and Signaling at μ and κ Opioid Receptors.Biochemistry · 2025Article
- Conformational Heterogeneity Underlying Divergent Signaling in Class A G Protein-Coupled Receptors.ACS pharmacology & translational science · 2025Review
- Structural and dynamic insights into the biased signaling mechanism of the human kappa opioid receptor.Nature communications · 2025Article
- Structural and dynamic studies uncover a distinct allosteric modulatory site at the μ-opioid receptor.bioRxiv : the preprint server for biology · 2025Article
- κ-Opioid Receptor Agonists as Robust Pain-Modulating Agents: Mechanisms and Therapeutic Potential in Pain Modulation.Journal of clinical medicine · 2025Review
- Development of Delta Opioid Receptor Antagonists Which Prevent Alzheimer's Disease-Like Pathology in the 5X-Familial Alzheimer's Disease [5XFAD] Mouse Model.ACS pharmacology & translational science · 2025Article
- Differential effects of sodium on agonist-induced conformational transitions and signaling at μ and κ opioid receptors.bioRxiv : the preprint server for biology · 2025Article
151 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 7 institutions in 3 countries.
Tao CheDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Susruta MajumdarMolecular Pharmacology Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Saheem A ZaidiDepartment of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
Pauline OndachiCenter for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
John D McCorvyDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Sheng WangDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Philip D MosierDepartment of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonweath University, Richmond, VA 23298, USA.
Rajendra UpretyMolecular Pharmacology Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Eyal VardyDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Brian E KrummDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Gye Won HanDepartment of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
Ming-Yue LeeDepartment 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.
Els PardonStructural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium; VIB-VUB Center for Structural Biology, VIB, 1050 Brussels, Belgium.
Jan SteyaertStructural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium; VIB-VUB Center for Structural Biology, VIB, 1050 Brussels, Belgium.
Xi-Ping HuangNational 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.
Ryan T StrachanDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Alexandra R TriboDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Gavril W PasternakMolecular Pharmacology Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
F Ivy CarrollCenter for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Raymond C StevensDepartment 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.
Vadim CherezovDepartment of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
Vsevolod KatritchDepartment 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.
Daniel WackerDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: dwacker@email.unc.edu.
Bryan L RothDepartment 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.
University of North Carolina at Chapel Hill · USUniversity of Southern California · USMemorial Sloan Kettering Cancer Center · USRTI International · USVrije Universiteit Brussel · BEArizona State University · USNational Institute of Mental Health · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MVirology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI David Darr · 1985 to 2026
$201.5MScreening CoreU19MH082441 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI CARON, MARC G., ROTH, BRYAN L. · 2007 to 2016
$15.2MStructure-Function of Opioid ReceptorsP01DA035764 · NIDA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ROTH, BRYAN L., STEVENS, RAYMOND C · 2014 to 2018
$7.1MSynthesis &Pharmacology of Novel Opiates and SystemsR01DA006241 · NIDA · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI PAN, YING-XIAN · 1990 to 2018
$6.4MTargeting and Trafficking of 5-HT2A Serotonin ReceptorsR01MH061887 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ROTH, BRYAN L. · 2000 to 2014
$4.5MDiterpines as Selective Kappa Opioid Receptor AgonistsR01DA017204 · NIDA · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ROTH, BRYAN L. · 2003 to 2014
$3.2MDeorphanizing the PeptidomeR01DA027170 · NIDA · UNIVERSITY OF MARYLAND BALTIMORE · PI LINDBERG, IRIS, ROTH, BRYAN L. · 2009 to 2012
$1.2MRational discovery of new DOR chemotypes to prevent addiction and overdoseR33DA038858 · NIDA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI KATRITCH, VSEVOLOD · 2017 to 2018
$719kAnalgesics targeting truncated 6transmembrane exon 11 variants of MOR-1 (6TM-E11)R33DA034106 · NIDA · SLOAN-KETTERING INST CAN RESEARCH · PI MAJUMDAR, SUSRUTA · 2014 to 2015
$596kAnalgesics targeting truncated 6transmembrane exon 11 variants of MOR-1 (6TM-E11)R21DA034106 · NIDA · SLOAN-KETTERING INST CAN RESEARCH · PI MAJUMDAR, SUSRUTA · 2012 to 2013
$443kRational discovery of new DOR chemotypes to prevent addiction and overdoseR21DA038858 · NIDA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI KATRITCH, VSEVOLOD · 2015 to 2016
$410kNCI NIH HHS P30 CA008748NCI NIH HHS P30 CA016086NIDA NIH HHS P01 DA035764NIDA NIH HHS R01 DA006241NIDA NIH HHS R01 DA017204NIDA NIH HHS R01 DA027170NIDA NIH HHS R21 DA034106NIDA NIH HHS R21 DA038858NIDA NIH HHS R33 DA034106NIDA NIH HHS R33 DA038858NIMH NIH HHS R01 MH061887NIMH NIH HHS U19 MH082441
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.
Indexed as
Molecular Docking SimulationAnalgesicsAnimalsBinding SitesHEK293 CellsHumansMolecular Dynamics SimulationMorphinansProtein BindingProtein StabilityReceptors, Opioid, kappaSf9 CellsSpodoptera17-cyclopropylmethyl-3-hydroxy-4,5-epoxy-7,8-en-6-((3'-iodo)benzamido)morphinanAnalgesicsMorphinansReceptors, Opioid, kappaactive stateaddictioncrystallographyGPCRmorphinannanobodyopioid receptorstructure-function
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