Structure [IFM]

Abstract :

Glycine receptors (GlyR) are pentameric ligand-gated ion channels (pLGIC) that mediate fast inhibitory neurotransmission in the spinal cord and brain stem by switching between discrete conformational states in response to neurotransmitter binding. GlyR dysfunction is linked to several disorders in human including temporal lobe epilepsy, hyperekplexia, and chronic inflammatory pain. Recent high-resolution structures by cryo-electron microscopy and X-ray crystallography have provided atomistic models for the open and closed states, but the discovery of two distinct open-channel forms questioned their physiological significance.

To help elucidating the nature of the active state, we used an original combination of simulation techniques spanning from Molecular Dynamics to computational electrophysiology (see Figure) to predict ion conductance and selectivity. Our analysis supports the conclusion that no available structure provides a correct representation of the physiologically active state. Also, the simulations captured a spontaneous transition to a distinct open channel form, which was stable, ion-conductive and selective in qualitative agreement with patch-clamp electrophysiology. These results provide a consistent functional annotation of structures in anionic pLGICs, which suggests a mechanistic interpretation of gating and desensitization. These studies are crucial for the rational exploration of allosteric modulation in pLGICs, which is the ultimate goal of CDP6.

 

Reference :

Adrien Cerdan, Nicolas Martin and Marco Cecchini︎

An Ion-Permeable State of the Glycine Receptor Captured by Molecular Dynamics

Structure, published: September 13, 2018 - DOI : https://doi.org/10.1016/j.str.2018.07.019

Contact chercheur :

Marco CECCHINI (mcecchini@unistra.fr), Équipe IFM (Laboratoire d’Ingénierie des Fonctions Moléculaires), Institut de Chimie, UMR 7177.