DOI: 10.1073/pnas.1918264117
论文题名: Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor
作者: Mafi A. ; Kim S.-K. ; Goddard W.A. ; III
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2020
卷: 117, 期: 28 起始页码: 16346
结束页码: 16355
语种: 英语
英文关键词: Biased agonists
; Molecular dynamics
; Nonbiased agonists
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
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. Citation statistics:
资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163434
Appears in Collections: 气候变化与战略
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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
Recommended Citation:
Mafi A.,Kim S.-K.,Goddard W.A.,et al. Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor[J]. Proceedings of the National Academy of Sciences of the United States of America,2020-01-01,117(28)