<br>κ-阿片受体中的配体和 G 蛋白选择性,Nature

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κ-阿片受体中的配体和 G 蛋白选择性
Nature ( IF 50.5 ) Pub Date : 2023-05-03 , DOI: 10.1038/s41586-023-06030-7
Jianming Han _{1,

2} , Jingying Zhang _{3,

4,

5,

6} , Antonina L Nazarova _{7,

8,

9} , Sarah M Bernhard _{1,

2} , Brian E Krumm ₁₀ , Lei Zhao ₁ , Jordy Homing Lam _{7,

8,

9} , Vipin A Rangari ₂ , Susruta Majumdar _{1,

2,

11} , David E Nichols ₁₂ , Vsevolod Katritch _{7,

8,

9} , Peng Yuan _{3,

4,

5,

6} , Jonathan F Fay ₁₃ , Tao Che _{1,

2,

11}

Affiliation

Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA.
Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St Louis and Washington University School of Medicine, St Louis, MO, USA.
Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA.
Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St Louis, MO, USA.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.
Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Washington University Pain Center, Washington University in St Louis, St Louis, MO, USA.
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
Department of Biochemistry and Molecular Biology, University of Maryland Baltimore, Baltimore, MD, USA.

κ-阿片受体 (KOR) 是一种非常理想的治疗靶点，不仅可以治疗疼痛，还可以治疗成瘾和情感障碍¹ 。然而，KOR 镇痛药的发展受到相关致幻副作用的阻碍² 。 KOR 信号传导的启动需要 G _i/o家族蛋白，包括常规亚型（G _i1 、G _i2 、G _i3 、G _oA和 G _oB ）和非常规亚型（G _z和 G _g ）。致幻剂如何通过 KOR 发挥作用以及 KOR 如何决定 G 蛋白亚型选择性尚不清楚。在这里，我们使用冷冻电子显微镜确定了具有多个 G 蛋白异源三聚体（G _i1 、 G _oA 、G _z和 G _{g ）}的复合物中 KOR 的活性态结构。 KOR-G 蛋白复合物与致幻性 Salvinorins 或高选择性 KOR 激动剂结合。这些结构的比较揭示了对 KOR-G 蛋白相互作用至关重要的分子决定因素以及控制 G _i/o家族亚型选择性和 KOR 配体选择性的关键要素。此外，四种 G 蛋白亚型在 KOR 上的激动剂结合上表现出本质上不同的结合亲和力和变构活性。这些结果为了解阿片类药物和 G 蛋白偶联特异性在 KOR 上的作用提供了见解，并为检查 KOR 通路选择性激动剂的治疗潜力奠定了基础。

"点击查看英文标题和摘要"

Ligand and G-protein selectivity in the κ-opioid receptor

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders¹. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects². The initiation of KOR signalling requires the G_i/o-family proteins including the conventional (G_i1, G_i2, G_i3, G_oA and G_oB) and nonconventional (G_z and G_g) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers—G_i1, G_oA, G_z and G_g—using cryo-electron microscopy. The KOR–G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR–G-protein interactions as well as key elements governing G_i/o-family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.

更新日期：2023-05-04

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