Final Report Summary - NEURO-PENTA (Structure of the brain serotonine 5-HT3 receptor and other mammalian Cys-loop receptors)
The objective of the Neuropenta project was to describe and understand, through structure, the pharmacology and conformational transitions in the Cys-loop family of receptors, focusing on the serotonin 5-HT3 receptor.
Our achievements can be briefly summarized as follows:
We have established the biochemical procedures to obtain large amounts of purified 5-HT3 receptor, which can then be used for crystallography and cryo-electron microscopy.
We have solved the structure, by X-ray diffraction, of the serotonin 5-HT3 receptor in complex with an inhibitory nanobody. This structure shed light on the ion permeation pathway and allowed, for the first time, the description of part of the intracellular domain.
We have then solved, by cryo-electron microscopy, the structures of the serotonin 5-HT3 receptor in complex with the anti-emetic drug tropisetron and in complex with serotonin. A total of four structures were obtained, which together deepen our mechanistic understanding of Cys-loop receptors at the molecular level, and also provide unprecedented detail on ligand binding.
The grant had a significant impact on the career development and re-integration of the fellow. Since the award of the CIG grant, the fellow has received several competitive grants, including an important grant from the European Research Council (ERC Starting grant). He has also established collaborations with the industrial sector. The current research group of the fellow is composed of six people; it has gained local and international recognition for its expertise in membrane protein structural studies. The fellow has been regularly invited to present at international meetings, and has authored three publications as corresponding author, including one published in Nature.