Exploring a new ligand binding site of G proteincoupled receptors

doi:10.1039/c8sc01680a

	Exploring a new ligand binding site of G proteincoupled receptors
	Chan, H. C. Stephen 1; Wang, Jingjing2 ; Palczewski, Krzysztof 3; Filipek, Slawomir 4; Vogel, Horst 5; Liu, Zhi-Jie2 ; Yuan, Shuguang 5
	2018-08-21
发表期刊	CHEMICAL SCIENCE (IF:7.6[JCR-2023],8.0[5-Year])
ISSN	2041-6520
卷号	9 期号:31
发表状态	已发表
DOI	10.1039/c8sc01680a
摘要	Identifying a target ligand binding site is an important step for structure-based rational drug design as shown here for G protein-coupled receptors (GPCRs), which are among the most popular drug targets. We applied long-time scale molecular dynamics simulations, coupled with mutagenesis studies, to two prototypical GPCRs, the M3 and M4 muscarinic acetylcholine receptors. Our results indicate that unlike synthetic antagonists, which bind to the classic orthosteric site, the endogenous agonist acetylcholine is able to diffuse into a much deeper binding pocket. We also discovered that the most recently resolved crystal structure of the LTB4 receptor comprised a bound inverse agonist, which extended its benzamidine moiety to the same binding pocket discovered in this work. Analysis on all resolved GPCR crystal structures indicated that this new pocket could exist in most receptors. Our findings provide new opportunities for GPCR drug discovery.
收录类别	EI ; SCIE ; SCI
语种	英语
资助项目	European COST Action[CM1207]
WOS研究方向	Chemistry
WOS类目	Chemistry, Multidisciplinary
WOS记录号	WOS:000442262400003
出版者	ROYAL SOC CHEMISTRY
EI入藏号	20183305684161
EI主题词	Ligands ; Molecular dynamics ; Proteins
EI分类号	Physical Chemistry:801.4 ; Organic Compounds:804.1 ; Crystal Lattice:933.1.1
WOS关键词	MUSCARINIC ACETYLCHOLINE-RECEPTOR ; COUPLED RECEPTORS ; DRUG DISCOVERY ; MOLECULAR-DYNAMICS ; STRUCTURAL BASIS ; P2Y(1) RECEPTOR ; FORCE-FIELD ; GPCR ; IDENTIFICATION ; ACTIVATION
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/27647
专题	生命科学与技术学院 iHuman研究所 iHuman研究所_PI研究组_刘志杰组生命科学与技术学院_博士生
通讯作者	Vogel, Horst; Liu, Zhi-Jie; Yuan, Shuguang
作者单位	1.Univ Bradford, Fac Life Sci, Bradford, W Yorkshire, England 2.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China 3.Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA 4.Univ Warsaw, Fac Chem, Biol & Chem Res Ctr, Warsaw, Poland 5.Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, 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,Wang, Jingjing,Palczewski, Krzysztof,et al. Exploring a new ligand binding site of G proteincoupled receptors[J]. CHEMICAL SCIENCE,2018,9(31).
APA	Chan, H. C. Stephen.,Wang, Jingjing.,Palczewski, Krzysztof.,Filipek, Slawomir.,Vogel, Horst.,...&Yuan, Shuguang.(2018).Exploring a new ligand binding site of G proteincoupled receptors.CHEMICAL SCIENCE,9(31).
MLA	Chan, H. C. Stephen,et al."Exploring a new ligand binding site of G proteincoupled receptors".CHEMICAL SCIENCE 9.31(2018).