Cryo-EM structures of inactive and active GABAB receptor  

作　　者：Chunyou Mao Cangsong Shen Chuntao Li Dan-Dan Shen Chanjuan Xu Shenglan Zhang Rui Zhou Qingya Shen Li-Nan Chen Jianfeng Liu Yan Zhang 

机构地区：[1]Department of Biophysics,and Department of Pathology of Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,310058,Zhejiang,China [2]MOE Frontier Science Center for Brain Research and Brain-Machine Integration,Zhejiang University School of Medicine,Hangzhou,310058,Zhejiang,China [3]Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province,Hangzhou,310058,Zhejiang,China [4]Key Laboratory of Molecular Biophysics of MOE,International Research Center for Sensory Biology and Technology of MOST,School of Life Science and Technology,Huazhong University of Science and Technology,Wuhan,430074,Hubei,China [5]Department of Biophysics,Zhejiang University School of Medicine,Hangzhou,310058,Zhejiang,China [6]Guangzhou Regenerative Medicine and Health Guangdong Laboratory,Guangzhou,510005,Guangdong,China

出　　处：《Cell Research》2020年第7期564-573,共10页细胞研究（英文版）

基　　金：We are grateful to H.Eric Xu for generously providing the plasmids of the heterotrimeric G protein.We thank S.Chang for technical support in cryo-EM data collection at the Center of Cryo-Electron Microscopy,Zhejiang University;Protein expression and purification were performed at the Protein Facilities,Zhejiang University School of Medicine with the support of C.Ma.J.L.was supported by the Ministry of Science and Technology(2018YFA0507003);the National Natural Science Foundation of China(81720108031,81872945,31721002 and 31420103909);the Program for Introducing Talents of Discipline to the Universities of the Ministry of Education(B08029);the Mérieux Research Grants Program of the Institut Mérieux.Y.Z.was supported by the National Natural Science Foundation of China(81922071);the National Key Basic Research Program of China(2019YFA0508800);Zhejiang Province Natural Science Fund for Excellent Young Scholars(LR19H310001);the Fundamental Research Funds for the Central Universities(2019XZZX001-01-06).

摘　　要：Metabotropic GABAB G protein-coupled receptor functions as a mandatory heterodimer of GB1 and GB2 subunits and mediates inhibitory neurotransmission in the central nervous system.Each subunit is composed of the extracellular Venus flytrap(VFT)domain and transmembrane(TM)domain.Here we present cryo-EM structures of full-length human heterodimeric GABAB receptor in the antagonist-bound inactive state and in the active state complexed with an agonist and a positive allosteric modulator in the presence of Gi1 protein at a resolution range of 2.8–3.0Å.Our structures reveal that agonist binding stabilizes the closure of GB1 VFT,which in turn triggers a rearrangement of TM interfaces between the two subunits from TM3-TM5/TM3-TM5 in the inactive state to TM6/TM6 in the active state and finally induces the opening of intracellular loop 3 and synergistic shifting of TM3,4 and 5 helices in GB2 TM domain to accommodate theα5-helix of Gi1.We also observed that the positive allosteric modulator anchors at the dimeric interface of TM domains.These results provide a structural framework for understanding class C GPCR activation and a rational template for allosteric modulator design targeting the dimeric interface of GABAB receptor.

关 键 词：domain. inactive RATIONAL 

分 类 号：Q51[生物学—生物化学]