Volume 30, No 7, Jul 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 7, July 2020: 564-573

ORIGINAL ARTICLES

Cryo-EM structures of inactive and active GABAB receptor

Chunyou Mao^1,2,3 , Cangsong Shen^4,5 , Chuntao Li⁵ , Dan-Dan Shen^1,2,3 , Chanjuan Xu^4,6 , Shenglan Zhang^4,6 , Rui Zhou⁴ , Qingya Shen^1,2,3 , Li-Nan Chen⁵ , Zhinong Jiang⁷ , Jianfeng Liu^4,6,* , Yan Zhang^1,2,3,5,*

¹Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058 Zhejiang, China
²MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058 Zhejiang, China
³Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou 310058 Zhejiang, China
⁴Key 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
⁵Department of Biophysics, Zhejiang University School of Medicine, Hangzhou 310058 Zhejiang, China
⁶Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005 Guangdong, China
⁷Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058 Zhejiang, China
^†These authors contributed equally: Chunyou Mao, Cangsong Shen
Correspondence: Jianfeng Liu(jfliu@mail.hust.edu.cn)Yan Zhang(zhang_yan@zju.edu.cn)

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 2.8–3.0 Å. 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 the α5-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.

https://doi.org/10.1038/s41422-020-0350-5

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