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DOI	10.1073/pnas.1918264117
	Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor
	Mafi A.; Kim S.-K.; Goddard W.A.; III
发表日期	2020
ISSN	0027-8424
起始页码	16346
结束页码	16355
卷号	117 期号:28
英文摘要	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. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Biased agonists; Molecular dynamics; Nonbiased agonists
语种	英语
scopus关键词	beta arrestin; beta arrestin 2; enkephalin[2 dextro alanine 4 methylphenylalanine 5 glycine]; G protein coupled receptor; inhibitory guanine nucleotide binding protein; morphine; mu opiate receptor; oliceridine; ((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine; beta arrestin 2; guanine nucleotide binding protein; mu opiate receptor; narcotic analgesic agent; protein binding; spiro compound; thiophene derivative; Article; binding affinity; binding competition; binding site; cytoplasm; human; molecular dynamics; molecular interaction; mouse; nonhuman; priority journal; protein binding; protein phosphorylation; protein structure; receptor binding; respiration depression; three-dimensional imaging; animal; cell membrane; chemistry; metabolism; phosphorylation; protein domain; signal transduction; Analgesics, Opioid; Animals; beta-Arrestin 2; Binding Sites; Cell Membrane; Cytoplasm; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; GTP-Binding Proteins; Humans; Mice; Molecular Dynamics Simulation; Morphine; Phosphorylation; Protein Binding; Protein Domains; Receptors, Opioid, mu; Signal Transduction; Spiro Compounds; Thiophenes
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160260
作者单位	Mafi, A., Materials and Process Simulation Center (139-74), California Institute of Technology, Pasadena, CA 91125, United States; Kim, S.-K., Materials and Process Simulation Center (139-74), California Institute of Technology, Pasadena, CA 91125, United States; Goddard, W.A., III, Materials and Process Simulation Center (139-74), California Institute of Technology, Pasadena, CA 91125, United States
推荐引用方式 GB/T 7714	Mafi A.,Kim S.-K.,Goddard W.A.,et al. Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor[J],2020,117(28).
APA	Mafi A.,Kim S.-K.,Goddard W.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).
MLA	Mafi A.,et al."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(2020).