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Structural studies of mammalian Cys-loop receptors

Periodic Reporting for period 3 - PentaBrain (Structural studies of mammalian Cys-loop receptors)

Reporting period: 2018-06-01 to 2019-11-30

The objective of the PentaBrain project is to understand in molecular terms pharmacology, gating, ion transport and conformational transitions of mammalian Cys-loop receptors.

The Cys-loop receptor family (also called pentameric ligand-gated ion channel family) directly mediates fast neurotransmission in the brain. Cys-loop receptors participate in many physiological functions (voluntary motion, memory, sleep, anxiety, reward, pain, ...) are involved in numerous pathologies (epilepsy, Parkinson and Alzheimer diseases, ...) and are the targets of a legion of psycho-active and therapeutic compounds (including nicotine, alcohol, benzodiazepines and barbiturates, anti-emetics, steroids, anesthetics, ...).

The PentaBrain project aims at delivering detailed 3D structures of Cys-loop receptors in the different conformations they adopt to perform their function. The ensemble of these structures will provide a framework to understand functional and mutagenesis data, a template for structural pharmacology, and will advance the mechanistic understanding of this class of receptors.
Four structures of the serotonin 5-HT3 receptor, ranging from 3.2 Angstroms to 4.5 Angstroms resolution, have been obtained. With an inhibited state, a putative pre-active state, and two putative distinct open states, these structures extend our understanding of the gating mechanisms of Cys-loop receptor. They also provide unprecedented details of serotonin binding and of orthosteric and allosteric site geometries.
Efforts will be made to complete the full mechanistic description of the 5-HT3 receptor, by trying to capture desensitized state(s) as well as trying kinetic structural experiments.
We also aim at unveiling structures of other Cys-loop receptors.