Molecular insights into the biased signaling mechanism of the μ-opioid receptor.
Molecular insights into the biased signaling mechanism of the μ-opioid receptor.
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DOI：
10.1016/j.molcel.2021.07.033
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发表时间：
2021-10-21
期刊：
影响因子：
16
通讯作者：
Sounier R
中科院分区：
文献类型：
--
作者：
Cong X;Maurel D;Déméné H;Vasiliauskaité-Brooks I;Hagelberger J;Peysson F;Saint-Paul J;Golebiowski J;Granier S;Sounier R
GPCR功能选择性为设计更安全的药物开辟了新的机会。配体通过调节受体的构象来协调GPCR信号级联反应。我们的研究为阿片配体通过β-阿片受体(μ-阿片受体，μOR)优先激活G蛋白途径的动力学机制提供了深入的见解。我们结合活细胞中的功能分析、溶液核磁共振波谱和增强采样分子动力学模拟来确定G蛋白偏向激动剂诱导的特定μ或构象。特别是，我们通过A类GPCRs中的保守基序描述了配体结合口袋和受体细胞内结构域之间的动态和变构通信。最引人注目的是，偏向的激动剂会触发细胞内环1和螺旋8区域的μ或构象变化，这可能会损害β-arrestin结合或信号转导。这些发现可能适用于其他GPCR家族，并提供关键的分子信息，有助于设计有偏见的配体。GPCRs的偏向配体提供了新的药物设计策略，以增强有益的药物作用，同时减少副作用。Cong等人。结合分子模拟、核磁共振波谱和功能分析揭示μ-阿片受体配体偏向的分子机制，为设计更好的阿片类止痛药提供结构依据。
GPCR functional selectivity open new opportunities for the design of safer drugs. Ligands orchestrate GPCR signaling cascades by modulating the receptor conformational landscape. Our study provides insights into the dynamic mechanism enabling opioid ligands to preferentially activate the G protein over the β-arrestin pathways through the μ-opioid receptor (μOR). We combine functional assays in living cells, solution NMR spectroscopy and enhanced-sampling molecular dynamic simulations to identify the specific μOR conformations induced by G protein-biased agonists. In particular, we describe the dynamic and allosteric communications between the ligand-binding pocket and the receptor intracellular domains, through conserved motifs in class A GPCRs. Most strikingly, the biased agonists trigger μOR conformational changes in the intracellular loop 1 and helix 8 domains, which may impair β-arrestin binding or signaling. The findings may apply to other GPCR families and provide key molecular information that could facilitate the design of biased ligands. Biased ligands of GPCRs offer new drug design strategies to enhance beneficial drug actions while reducing side effects. Cong et al. combined molecular simulations, NMR spectroscopy and functional assays to uncover the molecular mechanism of ligand bias in the μ-opioid receptor, which provides structural basis for designing better opioid analgesics.
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影响因子：
64.5
作者：
Huang, Shuya Kate;Pandey, Aditya;Duy Phuoc Tran;Villanueva, Nicolas L.;Kitao, Akio;Sunahara, Roger K.;Sljoka, Adnan;Prosser, R. Scott
通讯作者：
Prosser, R. Scott
影响因子：
64.5
作者：
Du, Yang;Duc, Nguyen Minh;Chung, Ka Young
通讯作者：
Chung, Ka Young
DOI：
10.1073/pnas.1110499108
发表时间：
2011-11-15
影响因子：
11.1
作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
通讯作者：
Shaw, David E.
影响因子：
7.7
作者：
Clark LD;Dikiy I;Chapman K;Rödström KE;Aramini J;LeVine MV;Khelashvili G;Rasmussen SG;Gardner KH;Rosenbaum DM
通讯作者：
Rosenbaum DM
影响因子：
64.8
作者：
Huang W;Manglik A;Venkatakrishnan AJ;Laeremans T;Feinberg EN;Sanborn AL;Kato HE;Livingston KE;Thorsen TS;Kling RC;Granier S;Gmeiner P;Husbands SM;Traynor JR;Weis WI;Steyaert J;Dror RO;Kobilka BK
通讯作者：
Kobilka BK