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bioRxiv · 10.1101/2023.06.16.545288

Structure and dynamics of differential ligand binding in the human {rho}-type GABA(A) receptor

Cowgill, J.·Fan, C.·Haloi, N.·Tobiasson, V.·Zhuang, Y.·Howard, R. J.·Lindahl, E.
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Abstract

The neurotransmitter {gamma}-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABAARs). Pharmacological properties of {rho}-type GABAARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here we present cryo-EM structures of a lipid-embedded human {rho}1 GABAAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin, and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of {rho}1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to {rho}-specific pharmaceutical design, and to our biophysical understanding of ligand-gated ion channels.

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Cowgill, J., Fan, C., Haloi, N., Tobiasson, V., Zhuang, Y., Howard, R. J., Lindahl, E.. 2023-06-17. Structure and dynamics of differential ligand binding in the human {rho}-type GABA(A) receptor. https://doi.org/10.1101/2023.06.16.545288

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