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Modelling and Molecular Dynamics Predict the Structure and Interactions of the Glycine Receptor Intracellular Domain.

Published version
Peer-reviewed

Repository DOI


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Authors

Thompson, James RE 
Beaudoin, Christopher A 
Lummis, Sarah CR 

Abstract

Glycine receptors (GlyRs) are glycine-gated inhibitory pentameric ligand-gated ion channels composed of α or α + β subunits. A number of structures of these proteins have been reported, but to date, these have only revealed details of the extracellular and transmembrane domains, with the intracellular domain (ICD) remaining uncharacterised due to its high flexibility. The ICD is a region that can modulate function in addition to being critical for receptor localisation and clustering via proteins such as gephyrin. Here, we use modelling and molecular dynamics (MD) to reveal details of the ICDs of both homomeric and heteromeric GlyR. At their N and C ends, both the α and β subunit ICDs have short helices, which are major sites of stabilising interactions; there is a large flexible loop between them capable of forming transient secondary structures. The α subunit can affect the β subunit ICD structure, which is more flexible in a 4α2:1β than in a 4α1:1β GlyR. We also explore the effects of gephyrin binding by creating GlyR models bound to the gephyrin E domain; MD simulations suggest these are more stable than the unbound forms, and again there are α subunit-dependent differences, despite the fact the gephyrin binds to the β subunit. The bound models also suggest that gephyrin causes compaction of the ICD. Overall, the data expand our knowledge of this important receptor protein and in particular clarify features of the underexplored ICD.

Description

Peer reviewed: True


Publication status: Published

Keywords

binding site, gephyrin, pentameric ligand-gated ion channel Cys-loop receptor, Receptors, Glycine, Molecular Dynamics Simulation, Carrier Proteins, Glycine

Journal Title

Biomolecules

Conference Name

Journal ISSN

2218-273X
2218-273X

Volume Title

13

Publisher

MDPI AG
Sponsorship
Medical Research Council (MR/L021676/1)