Structural basis of GABAB receptor–Gi protein coupling

Cangsong Shen, Chunyou Mao, Chanjuan Xu, Nan Jin, Huibing Zhang, Dan-Dan Shen, Qingya Shen, Xiaomei Wang, Tingjun Hou, Zhong Chen, Philippe Rondard, Jean-Philippe Pin (), Yan Zhang () and Jianfeng Liu ()
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Cangsong Shen: Huazhong University of Science and Technology (HUST)
Chunyou Mao: Zhejiang University School of Medicine
Chanjuan Xu: Huazhong University of Science and Technology (HUST)
Nan Jin: Huazhong University of Science and Technology (HUST)
Huibing Zhang: Zhejiang University School of Medicine
Dan-Dan Shen: Zhejiang University School of Medicine
Qingya Shen: Zhejiang University School of Medicine
Xiaomei Wang: Huazhong University of Science and Technology (HUST)
Tingjun Hou: Zhejiang University
Zhong Chen: Zhejiang Chinese Medical University
Philippe Rondard: Université de Montpellier, CNRS, INSERM
Jean-Philippe Pin: Université de Montpellier, CNRS, INSERM
Yan Zhang: Zhejiang University School of Medicine
Jianfeng Liu: Huazhong University of Science and Technology (HUST)

Nature, 2021, vol. 594, issue 7864, 594-598

Abstract: Abstract G-protein-coupled receptors (GPCRs) have central roles in intercellular communication1,2. Structural studies have revealed how GPCRs can activate G proteins. However, whether this mechanism is conserved among all classes of GPCR remains unknown. Here we report the structure of the class-C heterodimeric GABAB receptor, which is activated by the inhibitory transmitter GABA, in its active form complexed with Gi1 protein. We found that a single G protein interacts with the GB2 subunit of the GABAB receptor at a site that mainly involves intracellular loop 2 on the side of the transmembrane domain. This is in contrast to the G protein binding in a central cavity, as has been observed with other classes of GPCR. This binding mode results from the active form of the transmembrane domain of this GABAB receptor being different from that of other GPCRs, as it shows no outside movement of transmembrane helix 6. Our work also provides details of the inter- and intra-subunit changes that link agonist binding to G-protein activation in this heterodimeric complex.

Date: 2021
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DOI: 10.1038/s41586-021-03507-1

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