G蛋白偶联受体(G protein coupled receptors,GPCR)是目前研究最广泛的药物靶标蛋白.超过30%的已上市药物以GPCR为靶点.这一重要的跨膜蛋白家族及其分子结构和功能一直是各大制药公司和学术界的研究热点.近年来,GPCR X射线衍射晶体学方面取得了重大突破,已有30多个A类GPCR的高分辨率结构得到了解析.这为基于结构的药物设计和GPCR功能研究提供了结构依据,以及新的药物靶点和药物设计策略.利用这些结构,计算机模拟方法也在GPCR的结构和功能研究中得到了广泛应用,并在过去几年中取得了一些突破性的成果.这些研究进展深化了对GPCR的动态结构、配体识别和激活机制等方面的理解.简要回顾近年来对A类GPCR的结构和功能研究方面的最新进展,并特别对计算机辅助药物设计和分子模拟在这方面的应用进行重点讨论.%G protein-coupled receptors (GPCR) are the most studied drug targets, responding to over 30% of modern marketed drugs. The molecular structures and functions of this large family of transmembrane proteins have been the subject of heavy research by both the pharmaceutical industry and academia. Recent breakthroughs in GPCR crystallography have led to high-resolution structures of over 30 class A GPCR,which have provided the structural basis for rational drug design and functional studies, unveiling new drug targets and ligand design strategies. The structures also have been widely applied to computational approaches in GPCR research. A few groundbreaking studies in the last few years have significantly advanced the understanding in GPCR structures, dynamics, activation and ligand recognition. This mini-review summarizes the recent updates on class A GPCR structure and function, with a focus on the applications and perspectives of molecular modeling in GPCR ligand design.
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