How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?

NMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure...

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Main Authors: Zoltan Palmai, Kimberley Houenoussi, Sylvia Cohen-Kaminsky, Luba Tchertanov
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2018-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC6075769?pdf=render
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spelling doaj-c96373e004234e2bbfe43ebb7b1490152020-11-25T00:42:32ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01138e020123410.1371/journal.pone.0201234How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?Zoltan PalmaiKimberley HouenoussiSylvia Cohen-KaminskyLuba TchertanovNMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure of different states of the non-human NMDARs. Here we describe a model of a human NMDA receptor (hNMDAR) and its molecular dynamics (MD) before and after the binding of agonist ligands, glutamate and glycine. It is shown that the binding of ligands promotes a global reduction in molecular flexibility that produces a more tightly packed conformation than the unbound hNMDAR, and a higher cooperative regularity of moving. The ligand-induced synchronization of motion, identified on all structural levels of the modular hNMDA receptor is apparently a fundamental factor in channel gating. Although the time scale of the MD simulations (300 ns) was not sufficient to observe the complete gating event, the obtained data has shown the ligand-induced stabilization of hNMDAR that conforms the "going to be open state". We propose a mechanistic dynamic model of the ligand-dependent gating mechanism in the hNMDA receptor. At the binding of the ligands, the differently twisted conformations of the highly flexible receptor are stabilized in unique conformation with a linear molecular axis, which is a condition that is optimal for pore development. By searching the receptor surface, we have identified three new pockets, which are different from the pockets described in the literature as the potential and known positive allosteric modulator binding sites. A successful docking of two NMDAR modulators to their binding sites validates the model of a human NMDA receptor as a biological relevant target.http://europepmc.org/articles/PMC6075769?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Zoltan Palmai
Kimberley Houenoussi
Sylvia Cohen-Kaminsky
Luba Tchertanov
spellingShingle Zoltan Palmai
Kimberley Houenoussi
Sylvia Cohen-Kaminsky
Luba Tchertanov
How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?
PLoS ONE
author_facet Zoltan Palmai
Kimberley Houenoussi
Sylvia Cohen-Kaminsky
Luba Tchertanov
author_sort Zoltan Palmai
title How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?
title_short How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?
title_full How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?
title_fullStr How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?
title_full_unstemmed How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?
title_sort how does binding of agonist ligands control intrinsic molecular dynamics in human nmda receptors?
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2018-01-01
description NMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure of different states of the non-human NMDARs. Here we describe a model of a human NMDA receptor (hNMDAR) and its molecular dynamics (MD) before and after the binding of agonist ligands, glutamate and glycine. It is shown that the binding of ligands promotes a global reduction in molecular flexibility that produces a more tightly packed conformation than the unbound hNMDAR, and a higher cooperative regularity of moving. The ligand-induced synchronization of motion, identified on all structural levels of the modular hNMDA receptor is apparently a fundamental factor in channel gating. Although the time scale of the MD simulations (300 ns) was not sufficient to observe the complete gating event, the obtained data has shown the ligand-induced stabilization of hNMDAR that conforms the "going to be open state". We propose a mechanistic dynamic model of the ligand-dependent gating mechanism in the hNMDA receptor. At the binding of the ligands, the differently twisted conformations of the highly flexible receptor are stabilized in unique conformation with a linear molecular axis, which is a condition that is optimal for pore development. By searching the receptor surface, we have identified three new pockets, which are different from the pockets described in the literature as the potential and known positive allosteric modulator binding sites. A successful docking of two NMDAR modulators to their binding sites validates the model of a human NMDA receptor as a biological relevant target.
url http://europepmc.org/articles/PMC6075769?pdf=render
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