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配体效能调节μ阿片受体的构象动力学。

Ligand efficacy modulates conformational dynamics of the µ-opioid receptor.

机构信息

State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China.

Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China.

出版信息

Nature. 2024 May;629(8011):474-480. doi: 10.1038/s41586-024-07295-2. Epub 2024 Apr 10.

DOI:10.1038/s41586-024-07295-2
PMID:38600384
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11078757/
Abstract

The µ-opioid receptor (µOR) is an important target for pain management and molecular understanding of drug action on µOR will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance and single-molecule fluorescence resonance energy transfer, how ligand-specific conformational changes of µOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex. Interaction of β-arrestin-1 with the μOR core binding site appears less specific and occurs with much lower affinity than binding of G.

摘要

μ-阿片受体（μOR）是疼痛管理的重要靶点，对μOR 上药物作用的分子理解将有助于开发更好的治疗方法。在这里，我们使用双电子-电子共振和单分子荧光共振能量转移技术，展示了配体特异性的 μOR 构象变化如何在传感器水平上转化为广泛的内在效力。我们确定了受体胞质面的几种构象，它们在不同的时间尺度上相互转化，包括能够与 G 蛋白结合的预激活构象，以及显著降低三元复合物中 GDP 亲和力的完全激活构象。β-arrestin-1 与 μOR 核心结合位点的相互作用似乎不那么特异，亲和力也比 G 蛋白低得多。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/b4fd894c7922/41586_2024_7295_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/b9cc93c34dcb/41586_2024_7295_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/79047e75d280/41586_2024_7295_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/f8a77bc7e635/41586_2024_7295_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/5d36e34416da/41586_2024_7295_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/f70fd4815051/41586_2024_7295_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/586109071f86/41586_2024_7295_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/71ec931e4aa0/41586_2024_7295_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/13208d13e5c9/41586_2024_7295_Fig14_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a243/11078757/8308d8882f01/41586_2024_7295_Fig16_ESM.jpg

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