X-ray structure of the mouse serotonin 5-HT3 receptor

Neurotransmitter-gated ion channels of the Cys-loop receptor family mediate fast neurotransmission throughout the nervous system. The molecular processes of neurotransmitter binding, subsequent opening of the ion channel and ion permeation remain poorly understood. Here we present the X-ray structure of a mammalian Cys-loop receptor, the mouse serotonin 5-HT 3 receptor, at 3.5 Å resolution. The structure of the proteolysed receptor, made up of two fragments and comprising part of the intracellular domain, was determined in complex with stabilizing nanobodies. The extracellular domain reveals the detailed anatomy of the neurotransmitter binding site capped by a nanobody. The membrane domain delimits an aqueous pore with a 4.6 Å constriction. In the intracellular domain, a bundle of five intracellular helices creates a closed vestibule where lateral portals are obstructed by loops. This 5-HT 3 receptor structure, revealing part of the intracellular domain, expands the structural basis for understanding the operating mechanism of mammalian Cys-loop receptors. The first X-ray crystal structure of the mouse serotonin 5-HT 3 receptor, a pentameric ligand-gated ion channel, is similar to those of other Cys-loop receptors — though here electron density for part of the cytoplasmic domain, which is important for trafficking, synaptic localization, and modulation by cytoplasmic proteins, but not visible in previous structures, is also described. Serotonin 5-HT 3 receptor structure When the neurotransmitter serotonin binds to the 5-HT 3 receptor, the channel opens, leading to an excitatory response. This study reports the first X-ray crystal structure of the mouse serotonin 5-HT 3 receptor. The overall structure is similar to those of other Cys-loop receptors — although the authors were able to 'see' electron density for part of the cytoplasmic domain, which is important for trafficking, synaptic localization and modulation by cytoplasmic proteins; something that had not been visible in previous structures. Antagonists of the 5-HT 3 receptor are used as antiemetics (during chemotherapy for example) or to treat irritable bowel syndrome, so the hope is that this work could contribute to the design of new therapeutic agents.