美国德克萨斯大学西南医学中心Daniel M. Rosenbaum研究团队取得最新进展。他们揭示了脂膜中D2多巴胺受体（DRD2）-G蛋白复合物的结构。2020年6月11日，《自然》杂志发表了这一成果。
他们使用了冷冻电镜来阐明激动剂结合而活化DRD2-Gi的复合物重组到磷脂膜的结构。DRD2的细胞外配体结合位点响应激动剂结合而被重塑，在细胞外环2、跨膜结构域5（TM5）、TM6和TM7中发生构象变化，从而传播到细胞内Gi结合位点的开放。
DRD2-Gi结构代表嵌入在磷脂双层中的G蛋白偶联受体-G蛋白复合物的第一个实验模型，该模型可作为验证在以前的去垢剂结合结构中观察到的相互作用的基准。
该结构还揭示了膜嵌入复合物特有的相互作用，包括内部小叶中的螺旋8 burial，膜界面区域中有序的赖氨酸和精氨酸侧链，以及G蛋白在膜中的脂质锚定。他们激活的DRD2模型将有助于为多种人类中枢神经系统疾病提供亚型选择性DRD2配体的设计信息。
据介绍，DRD2是帕金森氏病和抗精神病药的治疗靶标。DRD2被内源性神经递质多巴胺和合成激动剂药物（如溴隐亭）激活，从而导致Gi的刺激和腺苷酸环化酶的抑制。
附：英文原文
Title: Structure of a D2 dopamine receptor–G-protein complex in a lipid membrane
Author: Jie Yin, Kuang-Yui M. Chen, Mary J. Clark, Mahdi Hijazi, Punita Kumari, Xiao-chen Bai, Roger K. Sunahara, Patrick Barth, Daniel M. Rosenbaum
Issue&Volume: 2020-06-11
Abstract: The D2 dopamine receptor (DRD2) is a therapeutic target for Parkinson’s disease1 and antipsychotic drugs2. DRD2 is activated by the endogenous neurotransmitter dopamine and synthetic agonist drugs such as bromocriptine3, leading to stimulation of Gi and inhibition of adenylyl cyclase. Here we used cryo-electron microscopy to elucidate the structure of an agonist-bound activated DRD2–Gi complex reconstituted into a phospholipid membrane. The extracellular ligand-binding site of DRD2 is remodelled in response to agonist binding, with conformational changes in extracellular loop 2, transmembrane domain 5 (TM5), TM6 and TM7, propagating to opening of the intracellular Gi-binding site. The DRD2–Gi structure represents, to our knowledge, the first experimental model of a G-protein-coupled receptor–G-protein complex embedded in a phospholipid bilayer, which serves as a benchmark to validate the interactions seen in previous detergent-bound structures. The structure also reveals interactions that are unique to the membrane-embedded complex, including helix 8 burial in the inner leaflet, ordered lysine and arginine side chains in the membrane interfacial regions, and lipid anchoring of the G protein in the membrane. Our model of the activated DRD2 will help to inform the design of subtype-selective DRD2 ligands for multiple human central nervous system disorders.
DOI: 10.1038/s41586-020-2379-5
Source: https://www.nature.com/articles/s41586-020-2379-5
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/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
