Glutamate and Glycine Binding to the NMDA Receptor

Alvin Yu, Albert Y Lau

Research output: Contribution to journalArticle

Abstract

At central nervous system synapses, agonist binding to postsynaptic ionotropic glutamate receptors (iGluRs) results in signaling between neurons. N-Methyl-D-aspartic acid (NMDA) receptors are a unique family of iGluRs that activate in response to the concurrent binding of glutamate and glycine. Here, we investigate the process of agonist binding to the GluN2A (glutamate binding) and GluN1 (glycine binding) NMDA receptor subtypes using long-timescale unbiased molecular dynamics simulations. We find that positively charged residues on the surface of the GluN2A ligand-binding domain (LBD) assist glutamate binding via a “guided-diffusion” mechanism, similar in fashion to glutamate binding to the GluA2 LBD of AMPA receptors. Glutamate can also bind in an inverted orientation. Glycine, on the other hand, binds to the GluN1 LBD via an “unguided-diffusion” mechanism, whereby glycine finds its binding site primarily by random thermal fluctuations. Free energy calculations quantify the glutamate- and glycine-binding processes. In the N-methyl-D-aspartic acid receptor family of ionotropic glutamate receptors, the agonist glutamate and its co-agonist glycine bind to their respective subunits by different dynamic mechanisms. Glutamate binding is assisted by structural features on the receptor surface. Glycine binding does not receive such assistance.

Original languageEnglish (US)
JournalStructure
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

N-Methylaspartate
Glycine
Glutamic Acid
Ionotropic Glutamate Receptors
Ligands
Excitatory Amino Acid Agonists
AMPA Receptors
aspartic acid receptor
Molecular Dynamics Simulation
Synapses
Central Nervous System
Hot Temperature
Binding Sites
Neurons

Keywords

  • free energy calculations
  • glutamate receptors
  • ligand binding
  • molecular dynamics simulations
  • NMDA receptors

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Glutamate and Glycine Binding to the NMDA Receptor. / Yu, Alvin; Lau, Albert Y.

In: Structure, 01.01.2018.

Research output: Contribution to journalArticle

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