Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor.
Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor.
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DOI：
10.1002/anie.201508794
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发表时间：
2015-12-21
期刊：
影响因子：
--
通讯作者：
Shimada I
中科院分区：
文献类型：
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作者：
Okude J;Ueda T;Kofuku Y;Sato M;Nobuyama N;Kondo K;Shiraishi Y;Mizumura T;Onishi K;Natsume M;Maeda M;Tsujishita H;Kuranaga T;Inoue M;Shimada I
G蛋白偶联受体（GPCR）配体在G蛋白和抑制蛋白途径中赋予不同程度的信号传导，这种现象称为“偏向信号传导”。然而，GPCR的偏向性信号传导的潜在机制仍然不清楚，尽管与G蛋白或抑制蛋白结合的GPCR的晶体结构是可用的。 在这项研究中，我们观察到的μ-阿片受体（μOR）的蛋氨酸残基在平衡和偏置的配体结合状态的NMR信号。我们发现，μOR的细胞内腔存在于封闭和多个开放构象之间的平衡，在跨膜螺旋3，5，6和7上耦合构象变化，并且每个开放构象的群体决定了每个配体结合状态下G蛋白和抑制蛋白介导的信号传导水平。这些发现提供了对GPCR的偏向性信号传导的深入了解，并将有助于开发刺激μOR并降低耐受性和依赖性的镇痛药。
G-protein-coupled receptor (GPCR) ligands impart differing degrees of signaling in the G-protein and arrestin pathways, in phenomena called “biased signaling”. However, the mechanism underlying the biased signaling of GPCRs is still unclear, although crystal structures of GPCRs bound to the G protein or arrestin are available. In this study, we observed the NMR signals from methionine residues of the μ-opioid receptor (μOR) in the balanced- and biased-ligand-bound states. We found that the intracellular cavity of μOR exists in an equilibrium between closed and multiple open conformations with coupled conformational changes on the transmembrane helices 3, 5, 6, and 7, and that the population of each open conformation determines the G-protein- and arrestin-mediated signaling levels in each ligand-bound state. These findings provide insight into the biased signaling of GPCRs and will be helpful for development of analgesics that stimulate μOR with reduced tolerance and dependence.