2. Academic Validation
  3. Structural Basis of GABAB Receptor Activation during Evolution

Structural Basis of GABAB Receptor Activation during Evolution

  • Adv Sci (Weinh). 2025 Jul 12:e09440. doi: 10.1002/advs.202509440.
Guofei Hou 1 2,  Shenglan Zhang 2,  Cangsong Shen 1 2 3,  Suyu Ji 4,  Binqian Zou 5,  Chanjuan Xu 1,  Liang Li 1,  Dandan Shen 4,  Jiayin Liang 5,  Haidi Chen 6,  Philippe Rondard 7,  Cheng Deng 6,  Jun He 5,  Yan Zhang 4 8 9,  Jianfeng Liu 1 2 3
Affiliations

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

GABAB 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 GABAB receptor is conserved during evolution remains unknown. Here, the cryogenic electron microscopy (cryo-EM) structures of the drosophila GABAB receptor in both antagonist-bound inactive state and GABA-bound active state in complex with Gi protein are reported. The drosophila GABAB receptor exhibits an asymmetric activation, mirroring its human homolog. However, a larger inactive interface prevents drosophila GABAB receptor constitutive activity. Four key residues, which are not conserved in drosophila GABAB 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 GABAB 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.

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