Molecular mechanism of biased signaling at the kappa opioid receptor

Amal El Daibani, Joseph M. Paggi, Kuglae Kim, Yianni D. Laloudakis, Petr Popov, Sarah M. Bernhard, Brian E. Krumm, Reid H. J. Olsen, Jeffrey Diberto, F. Ivy Carroll, Vsevolod Katritch, Bernhard Wünsch, Ron O. Dror () and Tao Che ()
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Amal El Daibani: Washington University School of Medicine
Joseph M. Paggi: Stanford University
Kuglae Kim: University of North Carolina School of Medicine
Yianni D. Laloudakis: Stanford University
Petr Popov: iMolecule, Skolkovo Institute of Science and Technology
Sarah M. Bernhard: Washington University School of Medicine
Brian E. Krumm: University of North Carolina School of Medicine
Reid H. J. Olsen: University of North Carolina School of Medicine
Jeffrey Diberto: University of North Carolina School of Medicine
F. Ivy Carroll: Research Triangle Institute
Vsevolod Katritch: University of Southern California
Bernhard Wünsch: Universität Münster
Ron O. Dror: Stanford University
Tao Che: Washington University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37041-7

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