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Computationally Discovered Potentiating Role of Glycans on NMDA Receptors

N-methyl-D-aspartate receptors (NMDARs) are glycoproteins in the brain central to learning and memory. The effects of glycosylation on the structure and dynamics of NMDARs are largely unknown. In this work, we use extensive molecular dynamics simulations of GluN1 and GluN2B ligand binding domains (L...

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Autores principales: Sinitskiy, Anton V., Stanley, Nathaniel H., Hackos, David H., Hanson, Jesse E., Sellers, Benjamin D., Pande, Vijay S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381272/
https://www.ncbi.nlm.nih.gov/pubmed/28378791
http://dx.doi.org/10.1038/srep44578
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author Sinitskiy, Anton V.
Stanley, Nathaniel H.
Hackos, David H.
Hanson, Jesse E.
Sellers, Benjamin D.
Pande, Vijay S.
author_facet Sinitskiy, Anton V.
Stanley, Nathaniel H.
Hackos, David H.
Hanson, Jesse E.
Sellers, Benjamin D.
Pande, Vijay S.
author_sort Sinitskiy, Anton V.
collection PubMed
description N-methyl-D-aspartate receptors (NMDARs) are glycoproteins in the brain central to learning and memory. The effects of glycosylation on the structure and dynamics of NMDARs are largely unknown. In this work, we use extensive molecular dynamics simulations of GluN1 and GluN2B ligand binding domains (LBDs) of NMDARs to investigate these effects. Our simulations predict that intra-domain interactions involving the glycan attached to residue GluN1-N440 stabilize closed-clamshell conformations of the GluN1 LBD. The glycan on GluN2B-N688 shows a similar, though weaker, effect. Based on these results, and assuming the transferability of the results of LBD simulations to the full receptor, we predict that glycans at GluN1-N440 might play a potentiator role in NMDARs. To validate this prediction, we perform electrophysiological analysis of full-length NMDARs with a glycosylation-preventing GluN1-N440Q mutation, and demonstrate an increase in the glycine EC50 value. Overall, our results suggest an intramolecular potentiating role of glycans on NMDA receptors.
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spelling pubmed-53812722017-04-10 Computationally Discovered Potentiating Role of Glycans on NMDA Receptors Sinitskiy, Anton V. Stanley, Nathaniel H. Hackos, David H. Hanson, Jesse E. Sellers, Benjamin D. Pande, Vijay S. Sci Rep Article N-methyl-D-aspartate receptors (NMDARs) are glycoproteins in the brain central to learning and memory. The effects of glycosylation on the structure and dynamics of NMDARs are largely unknown. In this work, we use extensive molecular dynamics simulations of GluN1 and GluN2B ligand binding domains (LBDs) of NMDARs to investigate these effects. Our simulations predict that intra-domain interactions involving the glycan attached to residue GluN1-N440 stabilize closed-clamshell conformations of the GluN1 LBD. The glycan on GluN2B-N688 shows a similar, though weaker, effect. Based on these results, and assuming the transferability of the results of LBD simulations to the full receptor, we predict that glycans at GluN1-N440 might play a potentiator role in NMDARs. To validate this prediction, we perform electrophysiological analysis of full-length NMDARs with a glycosylation-preventing GluN1-N440Q mutation, and demonstrate an increase in the glycine EC50 value. Overall, our results suggest an intramolecular potentiating role of glycans on NMDA receptors. Nature Publishing Group 2017-04-05 /pmc/articles/PMC5381272/ /pubmed/28378791 http://dx.doi.org/10.1038/srep44578 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Sinitskiy, Anton V.
Stanley, Nathaniel H.
Hackos, David H.
Hanson, Jesse E.
Sellers, Benjamin D.
Pande, Vijay S.
Computationally Discovered Potentiating Role of Glycans on NMDA Receptors
title Computationally Discovered Potentiating Role of Glycans on NMDA Receptors
title_full Computationally Discovered Potentiating Role of Glycans on NMDA Receptors
title_fullStr Computationally Discovered Potentiating Role of Glycans on NMDA Receptors
title_full_unstemmed Computationally Discovered Potentiating Role of Glycans on NMDA Receptors
title_short Computationally Discovered Potentiating Role of Glycans on NMDA Receptors
title_sort computationally discovered potentiating role of glycans on nmda receptors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381272/
https://www.ncbi.nlm.nih.gov/pubmed/28378791
http://dx.doi.org/10.1038/srep44578
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