Dynamic States of the Ligand-Free Class A G Protein-Coupled Receptor Extracellular Side

doi:10.1021/acs.biochem.8b00146

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	Dynamic States of the Ligand-Free Class A G Protein-Coupled Receptor Extracellular Side
	Zhang, Qiansen 1; Zhou, Mang 2; Zhao, Lifen 2; Jiang, Hualiang2 ; Yang, Huaiyu 1
刊名	BIOCHEMISTRY
	2018-08-14
卷号	57 期号:32 页码:4767-4775
ISSN号	0006-2960
DOI	10.1021/acs.biochem.8b00146
文献子类	Article
英文摘要	G protein-coupled receptors (GPCRs) make up the largest family of drug targets. The second extracellular loop (ECL2) and extracellular end of the third transmembrane helix (TM3) are basic structural elements of the GPCR ligand binding site. Currently, the disulfide bond between the two conserved cysteines in the ECL2 and TM3 is considered to be a basic GPCR structural feature. This disulfide bond has a significant effect on receptor dynamics and ligand binding. Here, molecular dynamics simulations and experimental results show that the two cysteines are distant from one another in the highest-population conformational state of ligand-free class A GPCRs and do not form a disulfide bond, indicating that the dynamics of the GPCR extracellular side are different from our conventional understanding. These surprising dynamics should have important effects on the drug binding process. On the basis of the two distinct ligand-free states, we suggest two kinetic processes for binding of ligands to GPCRs. These results challenge our commonly held beliefs regarding both GPCR structural features and ligand binding.
资助项目	National Natural Science Foundation of China[21422208] ; E-Institutes of Shanghai Municipal Education Commission[E09013] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund[U1501501]
WOS关键词	HUMAN P2Y(12) RECEPTOR ; CRYSTAL-STRUCTURE ; DISULFIDE BOND ; MOLECULAR-DYNAMICS ; ACTIVE METABOLITE ; FORCE-FIELD ; SURFACE EXPRESSION ; DRUG DISCOVERY ; ADP RECEPTOR ; ACTIVATION
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000442184600002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279620]
专题	生物技术药物研发中心（筹）药物发现与设计中心
通讯作者	Yang, Huaiyu
作者单位	1.East China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Qiansen,Zhou, Mang,Zhao, Lifen,et al. Dynamic States of the Ligand-Free Class A G Protein-Coupled Receptor Extracellular Side[J]. BIOCHEMISTRY,2018,57(32):4767-4775.
APA	Zhang, Qiansen,Zhou, Mang,Zhao, Lifen,Jiang, Hualiang,&Yang, Huaiyu.(2018).Dynamic States of the Ligand-Free Class A G Protein-Coupled Receptor Extracellular Side.BIOCHEMISTRY,57(32),4767-4775.
MLA	Zhang, Qiansen,et al."Dynamic States of the Ligand-Free Class A G Protein-Coupled Receptor Extracellular Side".BIOCHEMISTRY 57.32(2018):4767-4775.