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Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor

Mafi, Amirhossein and Kim, Soo-Kyung and Goddard, William A., III (2020) Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor. Proceedings of the National Academy of Sciences of the United States of America, 117 (28). pp. 16346-16355. ISSN 0027-8424. PMCID PMC7368253. https://resolver.caltech.edu/CaltechAUTHORS:20200630-070330108

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Abstract

Agonists to the μ-opioid G protein-coupled receptor (μOR) can alleviate pain through activation of G protein signaling, but they can also induce β-arrestin activation, leading to such side effects as respiratory depression. Biased ligands to μOR that induce G protein signaling without inducing β-arrestin signaling can alleviate pain while reducing side effects. However, the mechanism for stimulating β-arrestin signaling is not known, making it difficult to design optimum biased ligands. We use extensive molecular dynamics simulations to determine three-dimensional (3D) structures of activated β-arrestin2 stabilized by phosphorylated μOR bound to the morphine and D-Ala², N-MePhe⁴, Gly-ol]-enkephalin (DAMGO) nonbiased agonists and to the TRV130 biased agonist. For nonbiased agonists, we find that the β-arrestin2 couples to the phosphorylated μOR by forming strong polar interactions with intracellular loop 2 (ICL2) and either the ICL3 or cytoplasmic region of transmembrane (TM6). Strikingly, Gi protein makes identical strong bonds with these same ICLs. Thus, the Gi protein and β-arrestin2 compete for the same binding site even though their recruitment leads to much different outcomes. On the other hand, we find that TRV130 has a greater tendency to bind the extracellular portion of TM2 and TM3, which repositions TM6 in the cytoplasmic region of μOR, hindering β-arrestin2 from making polar anchors to the ICL3 or to the cytosolic end of TM6. This dramatically reduces the affinity between μOR and β-arrestin2.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1918264117DOIArticle
https://www.pnas.org/content/suppl/2020/06/27/1918264117.DCSupplementalPublisherSupporting Information
https://github.com/amafi-gpcr/Beta-arrestin2-mu-opioid-receptor-agonist-complex-PNAS-2020Related ItemData
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7368253/PubMed CentralArticle
ORCID:
AuthorORCID
Mafi, Amirhossein0000-0002-8366-6785
Kim, Soo-Kyung0000-0002-4498-5441
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2020 National Academy of Sciences. Published under the PNAS license. Contributed by William A. Goddard III, May 20, 2020 (sent for review October 18, 2019; reviewed by Robert J. Lefkowitz and Yinglong Miao). PNAS first published June 29, 2020. This work was partially supported through a Cargill Incorporated–Caltech Research Collaboration Project. It was also funded by gifts to the Materials and Process Simulation Center. We thank Brian Guthrie for helpful comments and suggestions. Author contributions: A.M. and W.A.G. designed research; A.M. and S.-K.K. performed research; A.M. and W.A.G. analyzed data; and A.M., S.-K.K., and W.A.G. wrote the paper. Reviewers: R.J.L., HHMI; and Y.M., University of Kansas. The authors declare no competing interest. Data deposition: Our optimized structure has been deposited in GitHub, https://github.com/amafi-gpcr/Beta-arrestin2-mu-opioid-receptor-agonist-complex-PNAS-2020. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1918264117/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
CargillUNSPECIFIED
CaltechUNSPECIFIED
Subject Keywords:biased agonists; nonbiased agonists; molecular dynamics
Other Numbering System:
Other Numbering System NameOther Numbering System ID
WAG1382
Issue or Number:28
PubMed Central ID:PMC7368253
Record Number:CaltechAUTHORS:20200630-070330108
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200630-070330108
Official Citation:Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor. Amirhossein Mafi, Soo-Kyung Kim, William A. Goddard. Proceedings of the National Academy of Sciences Jul 2020, 117 (28) 16346-16355; DOI: 10.1073/pnas.1918264117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104151
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Jun 2020 17:04
Last Modified:06 Aug 2020 18:31

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