Extended Data Figure 7: The neurotransmitter binding site.

a, Cartoon representation of a binding site at the interface between two subunits, viewed parallel to the membrane plane. Binding loops are indicated. b, Same view with solvent-accessible electrostatic potential mapped on the molecular surface, colour coded from red to blue (−10 to +10 kT e⁻¹, respectively). c, Same view with the surface removed for loop C, highlighting the electronegative binding site interior. d, The principal subunit Cα atoms were superimposed for epibatidine-bound AChBP²⁴ (Protein Data Bank accession 2BYQ, blue, r.m.s.d. = 1.07 Å) and α-conotoxin-bound AChBP⁷³ (Protein Data Bank accession 2C9T, grey, r.m.s.d. = 1.04 Å) on the extracellular domain of the 5-HT₃ receptor (orange). e, Top view of a slab (black line) of the superimposed structure. The loop C of the 5-HT₃ receptor adopts an intermediate conformation compared to the contracted loop of epibatidine-bound AChBP and the open loop of α-conotoxin-bound AChBP. f, View of the complementary subunits when principal subunits are superimposed, as in a and b. The β-sheet of the 5-HT₃ receptor clearly deviates from these of the AChBP, indicating a different quaternary organization. g, Top view of two 5-HT₃ receptor subunits with one VHH15 (cartoon and surface), with the neurotransmitter binding cavity represented as molecular surface (pink). The VHH15 covers the binding site, which remains accessible from below. h, Residues lining the neurotransmitter binding site are depicted on this scheme of the site, together with a sequence alignment, for each loop, of the mouse 5-HT₃ receptor with one human receptor of each subfamily.