Serotonin receptors (5-HT3AR) are cation-selective, neurotransmitter-gated, pentameric ion channels that play a crucial role in regulating cellular excitability. 5-HT3A receptor regulates gut movement and therefore drugs that inhibit its function are used to control vomiting reflexes. 5-HT3AR is a dynamic allosteric protein where binding of serotonin induces a global conformational change encompassing the ligand-binding extracellular domain (ECD), the transmembrane domain (TMD), and the intracellular domain (ICD). Although recent high resolution structures of other pentameric ion channels have highlighted fundamentals of the gating mechanism, there is still a lack of information on the conformational coupling between the different domains, especially the ICD. The ICD is implicated to play a role in gating, receptor trafficking, modulation of single channel conductance and desensitization kinetics. We determined two serotonin-bound structures of the full-length 5-HT3AR in distinct conformations at 3.32 Å and 3.89 Å resolutions that reveal the mechanism underlying channel activation. When compared to 5-HT3AR in the resting conformation, serotonin-bound states underwent a large twisting motion in the ECD and TMD leading to the opening of a 165 Å permeation pathway. In particular, lateral portals for ion permeation are created at the interface of the TMD and ICD highlighting an important role for the ICD in channel gating.

Conformational coupling across domains of the serotonin-bound full length 5HT3A receptor revealed by Cryo-EM

2019 Spring National Meeting

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