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

doi:10.1038/s41467-023-37041-7

Molecular mechanism of biased signaling at the kappa opioid receptor

Journal Article · Sat Mar 11 00:00:00 EST 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-37041-7· OSTI ID:2423523

El Daibani, Amal ^[1]; Paggi, Joseph M. ^[2]; Kim, Kuglae ^[3]; Laloudakis, Yianni D. ^[2]; Popov, Petr ^[4]; ^[1]; ^[5]; Olsen, Reid H. J. ^[5]; Diberto, Jeffrey ^[5]; Carroll, F. Ivy ^[6]; ^[7]; ^[8]; ^[2]; ^[9]

Washington Univ., St. Louis, MO (United States). School of Medicine; University of Health Sciences & Pharmacy, St. Louis, MO (United States)
Stanford Univ., CA (United States)
Yonsei Univ., Seoul (Korea, Republic of); University of North Carolina, Chapel Hill, NC (United States)
Skolkovo Institute of Science and Technology, Moscow (Russia)
University of North Carolina, Chapel Hill, NC (United States)
RTI International, Research Triangle Park, NC (United States)
Univ. of Southern California, Los Angeles, CA (United States)
Universität Münster (Germany)
University of Health Sciences & Pharmacy, St. Louis, MO (United States); Washington Univ., St. Louis, MO (United States). School of Medicine

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357; AC05-00OR22725

OSTI ID:: 2423523

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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