Structural Basis of GABAB Receptor Activation during Evolution

Guofei Hou; Shenglan Zhang; Cangsong Shen; Suyu Ji; Binqian Zou; Chanjuan Xu; Liang Li; Dandan Shen; Jiayin Liang; Haidi Chen; Philippe Rondard; Cheng Deng; Jun He; Yan Zhang; Jianfeng Liu

doi:10.1002/advs.202509440

Structural Basis of GABA_B Receptor Activation during Evolution

Adv Sci (Weinh). 2025 Jul 12:e09440. doi: 10.1002/advs.202509440. Online ahead of print.

Authors

Guofei Hou^{1

2}, Shenglan Zhang², Cangsong Shen^{1

2

3}, Suyu Ji⁴, Binqian Zou⁵, Chanjuan Xu¹, Liang Li¹, Dandan Shen⁴, Jiayin Liang⁵, Haidi Chen⁶, Philippe Rondard⁷, Cheng Deng⁶, Jun He⁵, Yan Zhang^{4

8

9}, Jianfeng Liu^{1

2

3}

Affiliations

¹ Cellular Signaling laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
² Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
³ Hubei Jiangxia Laboratory, Wuhan, Hubei, 430200, China.
⁴ Department of Biophysics and Department of Pathology of Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
⁵ CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
⁶ Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610213, China.
⁷ Institut de Génomique Fonctionnelle, Univ. Montpellier, CNRS, INSERM, Montpellier, 34094, France.
⁸ Liangzhu Laboratory, Zhejiang University, Hangzhou, 311121, China.
⁹ Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.

PMID: 40650551
DOI: 10.1002/advs.202509440

Abstract

GABA_B receptor is a Class C G protein-coupled receptor (GPCR) for γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter. It forms an obligatory heterodimer consisting of two subunits, GB1 and GB2. Whether the activation mechanism of the GABA_B receptor is conserved during evolution remains unknown. Here, the cryogenic electron microscopy (cryo-EM) structures of the drosophila GABA_B receptor in both antagonist-bound inactive state and GABA-bound active state in complex with G_i protein are reported. The drosophila GABA_B receptor exhibits an asymmetric activation, mirroring its human homolog. However, a larger inactive interface prevents drosophila GABA_B receptor constitutive activity. Four key residues, which are not conserved in drosophila GABA_B receptor, are responsible for the activity of the positive allosteric modulator in its human homolog. Whereas the intracellular loop 2 of drosophila GB2 (dGB2) is less involved, the ordered C terminus of dGB2 and its corresponding region in its human homolog are required for G protein coupling. These evolutionary variations provide a complete understanding of the activation mechanism of the GABA_B receptor and new insights for future development of allosteric modulators for medication and insecticides.

Keywords: GABA; GABAB receptor; GPCR (G protein‐coupled receptor); cryo‐EM; evolution.

Abstract

Grants and funding