Crystal structures of agonist-bound human cannabinoid receptor CB1

doi:10.1038/nature23272

	Crystal structures of agonist-bound human cannabinoid receptor CB1
	Hua, Tian1,2,3 ; Vemuri, Kiran 4,5; Nikas, Spyros P.4,5; Laprairie, Robert B.6,7; Wu, Yiran1 ; Qu, Lu 1,2,3; Pu, Mengchen1 ; Korde, Anisha 4,5; Jiang, Shan 4,5; Ho, Jo-Hao 6,7; Han, Gye Won 8,9; Ding, Kang1,3,10 ; Li, Xuanxuan 11; Liu, Haiguang 11; Hanson, Michael A.12; Zhao, Suwen1,10 ; Bohn, Laura M.6,7; Makriyannis, Alexandros 4,5; Stevens, Raymond C.1,8,9,10 ; Liu, Zhi-Jie1,2,10
	2017-07-27
发表期刊	NATURE (IF:50.5[JCR-2023],54.4[5-Year])
ISSN	0028-0836
卷号	547 期号:7664 页码:468-+
发表状态	已发表
DOI	10.1038/nature23272
摘要	The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC)(1). Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 angstrom and 2.95 angstrom resolution, respectively. The two CB1-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state(2), including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200(3.36) and Trp356(6.48) (superscripts denote Ballesteros-Weinstein numbering(3)) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Delta(9)-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.
收录类别	SCI
语种	英语
资助项目	NIH[R01DA041435] ; NIH[P01DA009158] ; NIH[R37DA023142]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000406358300039
出版者	NATURE PUBLISHING GROUP
WOS关键词	PROTEIN-COUPLED RECEPTORS ; HUMAN P2Y(12) RECEPTOR ; MEMBRANE-PROTEINS ; ACCURATE DOCKING ; GLIDE ; CHEMISTRY ; ANALOGS ; COMPLEX ; SYSTEM
原始文献类型	Article
通讯作者	Zhao, Suwen ; Bohn, Laura M. ; Makriyannis, Alexandros ; Liu, Zhi-Jie
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/2883
专题	iHuman研究所_公共科研平台_同步辐射线站生命科学与技术学院 iHuman研究所 iHuman研究所_特聘教授组_Andrej Sali组 iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所_PI研究组_刘志杰组 iHuman研究所_PI研究组_赵素文组 iHuman研究所_科学装置(X)_膜蛋白同步辐射线站生命科学与技术学院_硕士生 iHuman研究所_PI研究组_华甜组
通讯作者	Zhao, Suwen; Bohn, Laura M.; Makriyannis, Alexandros; Liu, Zhi-Jie
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 2.Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Northeastern Univ, Dept Pharmaceut Sci, Ctr Drug Discovery, Boston, MA 02115 USA 5.Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA 6.Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA 7.Scripps Res Inst, Dept Neurosci, Jupiter, FL 33458 USA 8.Univ Southern Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA 9.Univ Southern Calif, Bridge Inst, Dept Chem, Los Angeles, CA 90089 USA 10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 11.Beijing Computat Sci Res Ctr, Complex Syst Div, Beijing 100193, Peoples R China 12.GPCR Consortium, San Marcos, CA 92078 USA
第一作者单位	iHuman研究所
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Hua, Tian,Vemuri, Kiran,Nikas, Spyros P.,et al. Crystal structures of agonist-bound human cannabinoid receptor CB1[J]. NATURE,2017,547(7664):468-+.
APA	Hua, Tian.,Vemuri, Kiran.,Nikas, Spyros P..,Laprairie, Robert B..,Wu, Yiran.,...&Liu, Zhi-Jie.(2017).Crystal structures of agonist-bound human cannabinoid receptor CB1.NATURE,547(7664),468-+.
MLA	Hua, Tian,et al."Crystal structures of agonist-bound human cannabinoid receptor CB1".NATURE 547.7664(2017):468-+.