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Cryo-EM structures of ρ1 GABAA receptors with antagonist and agonist drugs

Author

Listed:
  • Chen Fan

    (KTH Royal Institute of Technology
    Stockholm University
    Shanghai Jiao Tong University School of Medicine)

  • John Cowgill

    (Stockholm University)

  • Rebecca J. Howard

    (KTH Royal Institute of Technology
    Stockholm University)

  • Erik Lindahl

    (KTH Royal Institute of Technology
    Stockholm University)

Abstract

The family of ρ-type GABAA receptors includes potential therapeutic targets in several neurological conditions, and features distinctive pharmacology compared to other subtypes. Here we report four cryo-EM structures with previously unresolved ligands, electrophysiology recordings, and molecular dynamics simulations to characterize binding and conformational impact of the drugs THIP (a non-opioid analgesic), CGP36742 (a phosphinic acid) and GABOB (an anticonvulsant) on a human ρ1 GABAA receptor. A distinctive binding pose of THIP in ρ1 versus α4β3δ GABAA receptors offers a rationale for its inverse effects on these subtypes. CGP36742 binding is similar to the canonical ρ-type inhibitor TPMPA, supporting a shared mechanism of action among phosphinic acids. Binding of GABOB is similar to GABA, but produces a mixture of partially-locked and desensitized states, likely underlying weaker agonist activity. Together, these results elucidate interactions of a ρ-type GABAA receptor with therapeutic drugs, offering mechanistic insights and a basis for further pharmaceutical development.

Suggested Citation

  • Chen Fan & John Cowgill & Rebecca J. Howard & Erik Lindahl, 2025. "Cryo-EM structures of ρ1 GABAA receptors with antagonist and agonist drugs," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61932-6
    DOI: 10.1038/s41467-025-61932-6
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    References listed on IDEAS

    as
    1. Yong Geng & Martin Bush & Lidia Mosyak & Feng Wang & Qing R. Fan, 2013. "Structural mechanism of ligand activation in human GABAB receptor," Nature, Nature, vol. 504(7479), pages 254-259, December.
    2. Andrija Sente & Rooma Desai & Katerina Naydenova & Tomas Malinauskas & Youssef Jounaidi & Jonas Miehling & Xiaojuan Zhou & Simonas Masiulis & Steven W. Hardwick & Dimitri Y. Chirgadze & Keith W. Mille, 2022. "Differential assembly diversifies GABAA receptor structures and signalling," Nature, Nature, vol. 604(7904), pages 190-194, April.
    3. Chen Fan & John Cowgill & Rebecca J. Howard & Erik Lindahl, 2024. "Divergent mechanisms of steroid inhibition in the human ρ1 GABAA receptor," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
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