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Computationally Discovered Potentiating Role of Glycans on NMDA Receptors.

ABSTRACT: 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.

SUBMITTER: Sinitskiy AV

PROVIDER: S-EPMC5381272 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Computationally Discovered Potentiating Role of Glycans on NMDA Receptors.

Sinitskiy Anton V AV Stanley Nathaniel H NH Hackos David H DH Hanson Jesse E JE Sellers Benjamin D BD Pande Vijay S VS

Scientific reports 20170405

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 ...[more]

PMID: 28378791

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Dataset Information

Computationally Discovered Potentiating Role of Glycans on NMDA Receptors.

Publications

Computationally Discovered Potentiating Role of Glycans on NMDA Receptors.

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