Cryo-EM structures of {rho}1 GABA(A) receptors with antagonist and agonist drugs

Abstract

The family of {rho}-type GABAA receptors includes potential therapeutic targets in several neurological conditions, and features distinctive pharmacology compared to other subtypes. Here we combine structures, recordings and simulations to characterize the binding and conformational impact of the drugs THIP (a non-opioid analgesic), CGP36742 (phosphinic acid inhibitor) and GABOB (an anticonvulsant) on a human {rho}1 GABAA receptor. We identify a distinctive binding pose of THIP in {rho}1 versus neuronal 4{beta}3{delta} GABAA receptors, offering a rationale for its inverse effects on these subtypes. CGP36742 binding is similar to the canonical {rho}-type inhibitor TPMPA, supporting a shared mechanism of action among phosphinic acid inhibitors. Binding of GABOB is similar to that of GABA, but produces a mixture of primed and desensitized states, likely underlying its weaker agonist activity. Together, these results elucidate interactions of a {rho}-type GABAA receptor with therapeutic drugs, offering mechanistic insights and a prospective basis for further pharmaceutical development.