Structural studies and drug discovery of G protein-coupled receptors

doi:10.1360/N972018-00307

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	Structural studies and drug discovery of G protein-coupled receptors
	Yang, Zhenlin 1; Wu, Beili1,2
刊名	Kexue Tongbao/Chinese Science Bulletin
	2018-05-15
卷号	63 期号:14 页码:1361-1373
ISSN号	0023074X
DOI	10.1360/N972018-00307
文献子类	Article
英文摘要	G protein-coupled receptors (GPCRs) constitute the largest membrane protein family in human body. Over 800 kinds of GPCRs have been characterized in human and are divided into Rhodopsin, Adhesion, Secretin, Glutamate and Frizzled/Taste 2 families. GPCRs can be stimulated by a variety of cell signal molecules, including hormones, neurotransmitters, ions, light etc. As the most widely distributed membrane proteins, GPCRs play important roles in almost all of the physiological activities and serve as drug targets for many diseases, such as cardiovascular diseases, central nervous disorders, inflammation, metabolic diseases and cancer. Despite their pivotal roles in the physiological and pharmaceutical fields, structure determination of GPCRs remains to be extremely challenging due to low protein yield when expressed in vitro, poor protein stability and multiple conformational states. To date, structures of 48 GPCRs have been determined, accounting for ~5% of characterized GPCRs. The most important developments of technique include fusion partner insertion and lipidic cubic phase (LCP) crystallization. Fusion partners, such as T4 lysozyme, thermo-stabilized apocytochrome b562RIL and flavodoxin etc, are inserted into the N terminus or intracellular loops to replace the unstable regions and provide hydrophilic contact for crystal packing. LCP is essential for crystallization as it mimics native environment of membrane proteins and is used to solve most of GPCR structures. Besides, stabilization mutations and disulfide-bond engineering are also widely used for GPCR structure determination. The X-ray free-electron laser (XFEL) and cryo-electron microscopy (EM) pave the way for obtaining high-resolution protein structure information from small size crystals or without the need for crystallization. According to the solved structures, GPCRs share a canonical seven transmembrane architecture despite their sequence diversity. However, the ligand binding pockets of different GPCRs vary in shape, size, location and electrostatics. The binding sites of orthostreric and allosteric ligands locate at extracellular, middle, intracellular and even outside of the transmembrane region. The diversity of the binding pockets provides structural basis for recognizing various ligands. Upon activation, GPCRs undergo conformational changes including a large outward movement of TM6 on the intracellular side, which exposes a pocket and engages downstream signal proteins. Three classes of downstream signal proteins have been reported, namely G proteins, G protein-coupled receptor kinases (GRKs) and arrestins. Approximate 34% of the US Food and Drug Administration approved drugs act at GPCRs. During 2011-2015, drugs targeting GPCRs accounted for about 27% of the global therapeutic drugs market share. Biologics, allosteric modulators and biased ligands are increasing in clinical trials targeting GPCRs, while major disease indications for GPCRs-targeted drugs show a shift from traditional popular areas such as allergy and hypertension toward diabetes, oncology and central nerves system disorders etc. Recent breakthroughs on GPCR structural determination provide insights into the mechanisms of ligand recognition and signal transduction, and facilitate structure-based drug design. However, more structural information is needed, including the interaction patterns of GPCR with other G proteins and basis of biased ligand signaling, to fully understand the superfamily membrane proteins. Here, we summarize the recent progresses on GPCR structural studies and drug discovery, and give suggestions for future research directions.
语种	中文
出版者	Chinese Academy of Sciences, P.O. Box 2871, Beijing, 100085, China
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266969]
专题	药物靶标结构与功能中心
通讯作者	Wu, Beili
作者单位	1.CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia and Medica, Chinese Academy of Sciences, Shanghai; 201203, China; 2.School of Life Science and Technology, ShanghaiTech University, Shanghai; 201210, China
推荐引用方式 GB/T 7714	Yang, Zhenlin,Wu, Beili. Structural studies and drug discovery of G protein-coupled receptors[J]. Kexue Tongbao/Chinese Science Bulletin,2018,63(14):1361-1373.
APA	Yang, Zhenlin,&Wu, Beili.(2018).Structural studies and drug discovery of G protein-coupled receptors.Kexue Tongbao/Chinese Science Bulletin,63(14),1361-1373.
MLA	Yang, Zhenlin,et al."Structural studies and drug discovery of G protein-coupled receptors".Kexue Tongbao/Chinese Science Bulletin 63.14(2018):1361-1373.