Crystal structures of agonist-bound human cannabinoid receptor CB1

被引：377

作者：

Hua, Tian ^{[1
,2
,3
]}

Vemuri, Kiran ^{[4
,5
]}

Nikas, Spyros P. ^{[4
,5
]}

Laprairie, Robert B. ^{[6
,7
]}

Wu, Yiran ^{[1
]}

Qu, Lu ^{[1
,2
,3
]}

Pu, Mengchen ^{[1
]}

Korde, Anisha ^{[4
,5
]}

Jiang, Shan ^{[4
,5
]}

Ho, Jo-Hao ^{[6
,7
]}

Han, Gye Won ^{[8
,9
]}

Ding, Kang ^{[1
,3
,10
]}

Li, Xuanxuan ^{[11
]}

Liu, Haiguang ^{[11
]}

Hanson, Michael A. ^{[12
]}

Zhao, Suwen ^{[1
,10
]}

Bohn, Laura M. ^{[6
,7
]}

Makriyannis, Alexandros ^{[4
,5
]}

Stevens, Raymond C. ^{[1
,8
,9
,10
]}

Liu, Zhi-Jie ^{[1
,2
,10
]}

机构：

[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

来源：

NATURE | 2017年 / 547卷 / 7664期

关键词：

MEMBRANE-PROTEINS; ACCURATE DOCKING; GLIDE; CHEMISTRY;

D O I：

10.1038/nature23272

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：468 / +

页数：17