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Molecular mechanism of biased signaling at the kappa opioid receptor.
El Daibani, Amal; Paggi, Joseph M; Kim, Kuglae; Laloudakis, Yianni D; Popov, Petr; Bernhard, Sarah M; Krumm, Brian E; Olsen, Reid H J; Diberto, Jeffrey; Carroll, F Ivy; Katritch, Vsevolod; Wünsch, Bernhard; Dror, Ron O; Che, Tao.
Afiliación
  • El Daibani A; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
  • Paggi JM; Center for Clinical Pharmacology, University of Health Sciences & Pharmacy and Washington University School of Medicine, Saint Louis, MO, USA.
  • Kim K; Department of Computer Science, Stanford University, Stanford, CA, USA.
  • Laloudakis YD; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • Popov P; Department of Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea.
  • Bernhard SM; Department of Computer Science, Stanford University, Stanford, CA, USA.
  • Krumm BE; iMolecule, Skolkovo Institute of Science and Technology, Moscow, Russia.
  • Olsen RHJ; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
  • Diberto J; Center for Clinical Pharmacology, University of Health Sciences & Pharmacy and Washington University School of Medicine, Saint Louis, MO, USA.
  • Carroll FI; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • Katritch V; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • Wünsch B; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • Dror RO; Research Triangle Institute, P.O. Box 12194, Research Triangle Park, NC, 27709, USA.
  • Che T; Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
Nat Commun ; 14(1): 1338, 2023 03 11.
Article en En | MEDLINE | ID: mdl-36906681
The κ-opioid receptor (KOR) has emerged as an attractive drug target for pain management without addiction, and biased signaling through particular pathways of KOR may be key to maintaining this benefit while minimizing side-effect liabilities. As for most G protein-coupled receptors (GPCRs), however, the molecular mechanisms of ligand-specific signaling at KOR have remained unclear. To better understand the molecular determinants of KOR signaling bias, we apply structure determination, atomic-level molecular dynamics (MD) simulations, and functional assays. We determine a crystal structure of KOR bound to the G protein-biased agonist nalfurafine, the first approved KOR-targeting drug. We also identify an arrestin-biased KOR agonist, WMS-X600. Using MD simulations of KOR bound to nalfurafine, WMS-X600, and a balanced agonist U50,488, we identify three active-state receptor conformations, including one that appears to favor arrestin signaling over G protein signaling and another that appears to favor G protein signaling over arrestin signaling. These results, combined with mutagenesis validation, provide a molecular explanation of how agonists achieve biased signaling at KOR.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores Opioides kappa / Morfinanos Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores Opioides kappa / Morfinanos Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article