Exploring the specific role of GPCRs dimerization in drug discovery

G蛋白偶联受体二聚化在药物开发中所发挥的特异性作用(英文)

G-protein-coupled receptors（GPCRs） are G-protein-coupled heptaspanning-membrane receptors.This group has thousands of members and is one of the important drug targets,accounting for 40%-50%of the drugs currently on the market.In the last decade,there has been a substantial re-evaluation of the assumption that GPCRs exist primarily as monomeric polypeptides, with support increasing for a model in which GPCRs can exist as homo- or hetero- dimers or even high-order oligomers.GPCRs dimers are hot research topics.Recent reports suggest that homo- or hetero- dimers exhibit ＂specific＂ functional properties which are distinct from monomeric receptors,involving agonist recognition,signaling,trafficking,and so on.Meanwhile,the occurrence of dimers with different pharmacological and signaling properties opens a completely new field in the search for novel drug targets useful to combat a variety of diseases and with potentially fewer side effects.In this paper,we will mainly review their specific structures and signal transduction,which help us reach for the high-hanging fruits in GPCRs drug discovery.

G蛋白偶联受体(GPCRs)是与G蛋白相偶联的七次跨膜受体,其成员有上千种,是重要的药物靶点之一。目前,GPCRs相关药物占市场上药物的40%-50%。在过去的十年中,对GPCRs主要以单体的形式存在着的这一假说做出了重新评估,大量事实证明GPCRs也能以同源或异源二聚体,甚至是高阶寡聚体的形式存在,比较热门的领域是GPCRs二聚化。最近研究表明同源或异源二聚化有不同于单体的特异功能特征,包括配体识别、信号转导、运输等。同时,在较少副作用治疗疾病的新药开发上,具有不同病理和信号转导途径的二聚体的出现开辟了新的领域。本综述主要介绍二聚体的特异结构及其特异的信号转导途径,从而有助于在GPCRs药物开发中取得丰硕的成果。