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

Chen Fan (), John Cowgill, Rebecca J. Howard () and Erik Lindahl ()
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Chen Fan: KTH Royal Institute of Technology
John Cowgill: Stockholm University
Rebecca J. Howard: KTH Royal Institute of Technology
Erik Lindahl: KTH Royal Institute of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61932-6

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