Conformational transitions of the serotonin 5-HT3 receptor

摘要

The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane^,: upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions, which result in transient opening of a pore permeable to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression. Despite the recent accumulation in pLGIC structures^–, no clear unifying view has emerged on conformational transitions involved in channel gating. Here we report four cryo-EM structures of the full-length mouse 5-HT3 receptor, ranging from 3.2 Å to 4.5 Å resolution, obtained in complex with the anti-emetic drug tropisetron, with serotonin, with serotonin and a positive allosteric modulator. The tropisetron-bound structure resembles those obtained with an inhibitory nanobody or without ligand. The other structures represent new conformations, including that of an open state and of two novel ligand-bound states. We present computational insights into the dynamics of the structures, their pore hydration and free-energy profiles; we characterize motions at the gate level and cation accessibility in the pore. Put together, the data deepen our understanding of the gating mechanism of pLGICs, while capturing ligand binding in unprecedented detail.