小柯机器人

美国圣路易斯华盛顿大学Tao Che等研究人员合作揭示κ-阿片受体的配体和G-蛋白的选择性。2023年5月3日，《自然》杂志在线发表了这项成果。

研究人员表示，κ-阿片受体（KOR）是一个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。然而，KOR镇痛剂的开发一直受到相关致幻副作用的阻碍。KOR信号的启动需要G_i/o家族蛋白，包括传统的（G_i1、G_i2、G_i3、G_oA和G_oB）和非传统的（G_z和G_g）亚型。人们对致幻剂如何通过KOR发挥其作用以及KOR如何决定G蛋白亚型的选择性还不是很清楚。

研究人员利用冷冻电镜确定了KOR与多种G-蛋白异构体（G_i1、G_oA、G_z和G_g）的复合物的活性状态结构。KOR-G-蛋白复合物与致幻的沙丁胺或高度选择性的KOR激动剂结合。对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，以及管理G_i/o-家族亚型选择性和KOR配体选择性的关键因素。此外，四种G-蛋白亚型对KOR的激动剂结合显示出本质上不同的结合亲和力和异构活性。这些结果为阿片类药物的作用和G-蛋白偶联在KOR的特异性提供了见解，并为研究KOR的途径选择性激动剂的治疗潜力奠定了基础。

附：英文原文

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

Author: Han, Jianming, Zhang, Jingying, Nazarova, Antonina L., Bernhard, Sarah M., Krumm, Brian E., Zhao, Lei, Lam, Jordy Homing, Rangari, Vipin A., Majumdar, Susruta, Nichols, David E., Katritch, Vsevolod, Yuan, Peng, Fay, Jonathan F., Che, Tao

Issue&Volume: 2023-05-03

Abstract: 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 Gi/o-family proteins including the conventional (Gi1, Gi2, Gi3, GoA and GoB) and nonconventional (Gz and Gg) 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—Gi1, GoA, Gz and Gg—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 Gi/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.

DOI: 10.1038/s41586-023-06030-7

Source: https://www.nature.com/articles/s41586-023-06030-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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