四川大学邵振华团队的最新研究揭示了DRD1-Gs信号复合物的配体识别和变构调节。这一研究成果于2021年2月18日发表在国际学术期刊《细胞》上。
研究人员解析了多巴胺D1受体（DRD1）与Gs异三聚体偶联的五个冷冻电镜（cryo-EM）结构，该结构与三个基于邻苯二酚的激活剂、一个非邻苯二酚激活剂和一个正构调节剂结合。这些结构表明，极性相互作用网络对于儿茶酚胺样激活剂的识别必不可少，而扩展结合袋中的特定基序则将D1-与D2-样受体区分开。
此外，通过稳定正构位点的内源性多巴胺相互作用，研究表明内表面口袋处的变构结合提高了DRD1的活性。DRD1-Gs接口具有关键特性，可作为G蛋白偶联的决定因素。总的来说，该研究提供了对DRD1配体识别、变构调节和G蛋白偶联机制的结构理解。
据悉，D1和D2样多巴胺受体是各种神经系统综合症以及心血管和肾脏疾病的重要治疗靶点。
附：英文原文
Title: Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes
Author: Peng Xiao, Wei Yan, Lu Gou, Ya-Ni Zhong, Liangliang Kong, Chao Wu, Xin Wen, Yuan Yuan, Sheng Cao, Changxiu Qu, Xin Yang, Chuan-Cheng Yang, Anjie Xia, Zhenquan Hu, Qianqian Zhang, Yong-Hao He, Dao-Lai Zhang, Chao Zhang, Gui-Hua Hou, Huanxiang Liu, Lizhe Zhu, Ping Fu, Shengyong Yang, Daniel M. Rosenbaum, Jin-Peng Sun, Yang Du, Lei Zhang, Xiao Yu, Zhenhua Shao
Issue&Volume: 2021/02/18
Abstract: Dopamine receptors, including D1- and D2-like receptors, are important therapeutictargets in a variety of neurological syndromes, as well as cardiovascular and kidneydiseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of thedopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-basedagonists, a non-catechol agonist, and a positive allosteric modulator for endogenousdopamine. These structures revealed that a polar interaction network is essentialfor catecholamine-like agonist recognition, whereas specific motifs in the extendedbinding pocket were responsible for discriminating D1- from D2-like receptors. Moreover,allosteric binding at a distinct inner surface pocket improved the activity of DRD1by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interfacerevealed key features that serve as determinants for G protein coupling. Together,our study provides a structural understanding of the ligand recognition, allostericregulation, and G protein coupling mechanisms of DRD1.
DOI: 10.1016/j.cell.2021.01.028
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00071-4