Fig. 4: Mechanism of neurosteroid potentiation.

The schematic on the left is based on the full-length recombinant receptor structure (PDB 6I53), whereas the schematic on the right is based on the two-Fab-APG structure from this study. GABA interacts with the receptor at the ECD β⁺/α⁻ pocket, inducing anticlockwise rotations of the ECD that reorganize the TMD for Cl⁻ ion conduction. Neurosteroids bind to the receptor at the TMD β⁺/α⁻ pocket, causing additional anticlockwise ECD rotation and acting as a diagonal brace to stabilize the TMD open-channel conformation. Annular lipids insert their acyl tails between the M3 and M1 helices of adjacent subunits, offering further stabilization of an open-channel conformation.