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Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.
Che, Tao; Majumdar, Susruta; Zaidi, Saheem A; Ondachi, Pauline; McCorvy, John D; Wang, Sheng; Mosier, Philip D; Uprety, Rajendra; Vardy, Eyal; Krumm, Brian E; Han, Gye Won; Lee, Ming-Yue; Pardon, Els; Steyaert, Jan; Huang, Xi-Ping; Strachan, Ryan T; Tribo, Alexandra R; Pasternak, Gavril W; Carroll, F Ivy; Stevens, Raymond C; Cherezov, Vadim; Katritch, Vsevolod; Wacker, Daniel; Roth, Bryan L.
  • Che T; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Majumdar S; Molecular Pharmacology Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Zaidi SA; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
  • Ondachi P; Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
  • McCorvy JD; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Wang S; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Mosier PD; Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonweath University, Richmond, VA 23298, USA.
  • Uprety R; Molecular Pharmacology Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Vardy E; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Krumm BE; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Han GW; Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
  • Lee MY; 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 Environme
  • Pardon E; Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium; VIB-VUB Center for Structural Biology, VIB, 1050 Brussels, Belgium.
  • Steyaert J; Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium; VIB-VUB Center for Structural Biology, VIB, 1050 Brussels, Belgium.
  • Huang XP; 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.
  • Strachan RT; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Tribo AR; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • Pasternak GW; Molecular Pharmacology Program and Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Carroll FI; Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
  • Stevens RC; 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.
  • Cherezov V; Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
  • Katritch V; 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.
  • Wacker D; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: dwacker@email.unc.edu.
  • Roth BL; 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
Cell ; 172(1-2): 55-67.e15, 2018 01 11.
Article en En | MEDLINE | ID: mdl-29307491
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores Opioides kappa / Simulación del Acoplamiento Molecular Límite: Animals / Humans Idioma: En Año: 2018 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores Opioides kappa / Simulación del Acoplamiento Molecular Límite: Animals / Humans Idioma: En Año: 2018 Tipo del documento: Article