The ρ-type GABAA receptors are inhibitory pentameric ligand-gated ion channels with distinctive pharmacology from the canonical synaptic receptors, with high relevance in vision, cognition, and neurological disease. Despite their therapeutic potential, the molecular basis of ligand action at these receptors has remained poorly understood. Based on our recent determination of their structure, we have combined cryo-electron microscopy, electrophysiology, and molecular dynamics simulations to resolve how agonists and antagonists modulate the human ρ1 GABA A receptor. In particular, new high-resolution cryo-EM structures capture the binding of three drugs of clinical interest: the analgesic THIP (gaboxadol), the phosphinic acid CGP36742, and the anticonvulsant GABOB. Each revealed a different influence on the canonical “loop C lockdown” transition that governs channel gating. THIP and CGP36742 adopt steric poses that prevent full loop C closure, stabilizing resting-like states and explaining their antagonist properties. In contrast, GABOB engages the orthosteric site in a manner similar to GABA but stabilizes a heterogeneous ensemble of partially locked and desensitized states, consistent with its weaker agonist activity. Comparison with other GABA A subtypes highlights how subtle sequence differences remodel the orthosteric site, rationalizing the subtype-specific and even opposing effects of the same ligand across receptor families. These insights extend to the selectivity of phosphinic acid inhibitors between GABA A and GABA B receptors, suggesting a structural framework for future drug design. Together, these results define the structural and dynamic basis of agonism and antagonism in ρ-type GABA A receptors. By linking binding poses to conformational transitions, they illuminate how drug scaffolds can be tuned for subtype selectivity and efficacy. More broadly, this work provides a mechanistic blueprint for exploiting the pharmacological diversity of GABA A receptors in therapeutic development in general, and subtype-specific targeting in particular.
Fan et al. (Sun,) studied this question.