Enhancing the Signaling of GPCRs via Orthosteric Ions

doi:10.1021/acscentsci.9b01247

	Enhancing the Signaling of GPCRs via Orthosteric Ions
	Chan, H. C. Stephen 2; Xu, Yueming1 ; Tan, Liang1 ; Vogel, Horst 2,3; Cheng, Jianjun1 ; Wu, Dong1 ; Yuan, Shuguang 2
	2020-02-26
发表期刊	ACS CENTRAL SCIENCE
ISSN	2374-7943
EISSN	2374-7951
卷号	6 期号:2 页码:274-282
发表状态	已发表
DOI	10.1021/acscentsci.9b01247
摘要	G protein-coupled receptors play essential roles in cellular processes such as neuronal signaling, vision, olfaction, tasting, and metabolism. As GPCRs are the most important drug targets, understanding their interactions with ligands is of utmost importance for discovering related new medicines. In many GPCRs, an allosteric sodium ion next to the highly conserved residue D-2.50 has been proposed to stabilize the inactive receptor state by mediating interactions between transmembrane helices. Here, we probed the existence of internal and functionally important sodium ions in the dopamine D2 receptor, using molecular dynamics simulations. Besides a new sodium ion at the allosteric ligand binding site, we discovered an additional sodium ion, located close to the orthosteric ligand binding site. Through cell-based activation assays, the signaling of D2 receptor with site-specific mutations was tested against a series of chemically modified agonists. We concluded an important structural role of this newly discovered orthosteric sodium ion in modulating the receptor signaling: It enables the coordination of a polar residue in the ligand binding site with an appropriately designed agonist molecule. An identical interaction was also observed in a recently released high-resolution crystal structure of mu-opioid receptor, which was reresolved in this work. Probably because of similar interactions, various metal ions have been found to increase the signaling of many other GPCRs. This unique principle and strategy could be used to optimize the drug activity of GPCR. Our findings open a new mechanistic opportunity of GPCR signaling and help design the next generation of drugs targeting GPCRs.
收录类别	SCI ; SCIE ; EI
语种	英语
资助项目	Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw[GB70-3] ; Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw[GB71-3]
WOS研究方向	Chemistry
WOS类目	Chemistry, Multidisciplinary
WOS记录号	WOS:000517832800023
出版者	AMER CHEMICAL SOC
EI入藏号	20200608148171
EI主题词	Amines ; Crystal structure ; Ligands ; Metal ions ; Molecular dynamics ; Signaling ; Sodium
EI分类号	Biomedical Engineering:461.1 ; Metallurgy:531.1 ; Alkali Metals:549.1 ; Physical Chemistry:801.4 ; Organic Compounds:804.1 ; Crystal Lattice:933.1.1
WOS关键词	DOPAMINE-RECEPTORS ; ALLOSTERIC SODIUM ; OPIOID RECEPTORS ; STRUCTURAL BASIS ; BINDING-SITES ; FORCE-FIELD ; METAL-IONS ; PROTEIN ; D2 ; ACTIVATION
原始文献类型	Article
引用统计	被引频次：21[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/119046
专题	iHuman研究所_PI研究组_程建军组 iHuman研究所_公共科研平台_IT平台 iHuman研究所_PI研究组_陶厚朝组
通讯作者	Cheng, Jianjun; Wu, Dong; Yuan, Shuguang
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 2.Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen 518055, Peoples R China 3.Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, CH-1015 Lausanne, Switzerland
通讯作者单位	iHuman研究所
推荐引用方式 GB/T 7714	Chan, H. C. Stephen,Xu, Yueming,Tan, Liang,et al. Enhancing the Signaling of GPCRs via Orthosteric Ions[J]. ACS CENTRAL SCIENCE,2020,6(2):274-282.
APA	Chan, H. C. Stephen.,Xu, Yueming.,Tan, Liang.,Vogel, Horst.,Cheng, Jianjun.,...&Yuan, Shuguang.(2020).Enhancing the Signaling of GPCRs via Orthosteric Ions.ACS CENTRAL SCIENCE,6(2),274-282.
MLA	Chan, H. C. Stephen,et al."Enhancing the Signaling of GPCRs via Orthosteric Ions".ACS CENTRAL SCIENCE 6.2(2020):274-282.