Molecular dynamics simulations of the ligand-binding domain of the ionotropic glutamate receptor GluR2.

Abstract:

:Ionotropic glutamate receptors are essential for fast synaptic nerve transmission. Recent x-ray structures for the ligand-binding (S1S2) region of the GluR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive receptor have suggested how differences in protein/ligand interactions may determine whether a ligand will behave as a full agonist. We have used multiple molecular dynamics simulations of 2-5 ns duration to explore the structural dynamics of GluR2 S1S2 in the presence and absence of glutamate and in a complex with kainate. Our studies indicate that not only is the degree of domain closure dependent upon interactions with the ligand, but also that protein/ligand interactions influence the motion of the S2 domain with respect to S1. Differences in domain mobility between the three states (apo-S1S2, glutamate-bound, and kainate-bound) are surprisingly clear-cut. We discuss how these changes in dynamics may provide an explanation relating the mechanism of transmission of the agonist-binding event to channel opening. We also show here how the glutamate may adopt an alternative mode of binding not seen in the x-ray structure, which involves a key threonine (T480) side chain flipping into a new conformation. This new conformation results in an altered pattern of hydrogen bonding at the agonist-binding site.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Arinaminpathy Y,Sansom MS,Biggin PC

doi

10.1016/S0006-3495(02)75430-1

subject

Has Abstract

pub_date

2002-02-01 00:00:00

pages

676-83

issue

2

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(02)75430-1

journal_volume

82

pub_type

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