A1 Refereed original research article in a scientific journal
Full and Partial Agonism of Ionotropic Glutamate Receptors Indicated by Molecular Dynamics Simulations
Authors: Postila PA, Ylilauri M, Pentikainen OT
Publisher: AMER CHEMICAL SOC
Publication year: 2011
Journal: Journal of Chemical Information and Modeling
Journal name in source: JOURNAL OF CHEMICAL INFORMATION AND MODELING
Journal acronym: J CHEM INF MODEL
Volume: 51
Issue: 5
First page : 1037
Last page: 1047
Number of pages: 11
ISSN: 1549-9596
DOI: https://doi.org/10.1021/ci2000055
Abstract
Ionotropic glutamate receptors (iGluRs) are synaptic proteins that facilitate signal transmission in the central nervous system. Extracellular iGluR cleft closure is linked to receptor activation; however, the mechanism underlying partial agonism is not entirely understood. Full agonists close the bilobed ligand-binding domain (LBD), while antagonists prevent closure; the transmembrane ion channel either opens or stays closed, respectively. Although some bulky partial agonists produce intermediate iGluR-LBD closure, the available crystal structures also imply that the cleft can be shut with certain partial agonists. Recently, we have shown that the iGluR-LBD closure stage can be recreated by inserting a ligand into the closed cleft and simulating the ligand-receptor complex with molecular dynamics. Our simulations indicate that partial agonist binding does not necessarily prevent full receptor cleft closure; instead, it destabilizes cleft closure. Interdomain hydrogen bonds were studied thoroughly, and one hydrogen bond, in particular, was consistently disrupted by bound partial agonists. Accordingly, the simulation protocol presented here can be used to categorize compounds in silico as partial or full agonists for iGluRs.
Ionotropic glutamate receptors (iGluRs) are synaptic proteins that facilitate signal transmission in the central nervous system. Extracellular iGluR cleft closure is linked to receptor activation; however, the mechanism underlying partial agonism is not entirely understood. Full agonists close the bilobed ligand-binding domain (LBD), while antagonists prevent closure; the transmembrane ion channel either opens or stays closed, respectively. Although some bulky partial agonists produce intermediate iGluR-LBD closure, the available crystal structures also imply that the cleft can be shut with certain partial agonists. Recently, we have shown that the iGluR-LBD closure stage can be recreated by inserting a ligand into the closed cleft and simulating the ligand-receptor complex with molecular dynamics. Our simulations indicate that partial agonist binding does not necessarily prevent full receptor cleft closure; instead, it destabilizes cleft closure. Interdomain hydrogen bonds were studied thoroughly, and one hydrogen bond, in particular, was consistently disrupted by bound partial agonists. Accordingly, the simulation protocol presented here can be used to categorize compounds in silico as partial or full agonists for iGluRs.
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