Extended Data Fig. 8: Structural motif and reorganization at the ECD–TMD interface.

a, b, Key interacting charged residues R218 (pre-M1, key in gating^72,73,74), E53 (loop β1–β2), E186 (loop β8–β9, conserved only in cationic eukaryotic receptors) and D145 (Cys loop)—represented as purple sticks—are sandwiched between conserved essential aromatic residues (FPF motif of the Cys loop, W187 of β8–β9 and Y223 of M1), represented as yellow sticks and dots. Lower in the membrane, the strictly conserved P230—represented as spheres—enables M1 to kink. This structural organization is common to all pLGICs of known structure. Orientations of the views are indicated on the topology scheme. c, d, Side and top views depicting the concerted relative positions of the Cys-loop FPF ‘wedge’, represented as sticks, of transmembrane helices and of the β8–β9 loop. Compared to the inhibited structure, the wedge moves towards and pushes on M1 and also moves towards M4 in I1, I2 and F. F presents the biggest re-organization in this zone: M1, the M2–M3 loop and M3 follow the motion of the FPF motif, and M2 moves away from the pore axis (that is, to the back in the view in c and to the top in d). e, Conservation of the ‘sandwich’ structural motif in representative pLGIC structures. The aromatic top and bottom layers are represented as spheres (yellow, Cys loop; orange, β8–β9 loop and pre-M1 residue) whereas the central layer of charges is depicted as sticks. Note that in anionic receptors and GLIC, the charge of β8–β9 is absent (noted with a star). f, Sequence alignment of the motif residues in representative pLGIC structures.