Structural Basis of Functional Transitions in Mammalian NMDA Receptors

Cell. 2020 Jul 23;182(2):357-371.e13. doi: 10.1016/j.cell.2020.05.052. Epub 2020 Jun 30.


Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of GluN1 and GluN2 subunits, which bind glycine and glutamate, respectively, to activate their ion channels. Despite importance in brain physiology, the precise mechanisms by which activation and inhibition occur via subunit-specific binding of agonists and antagonists remain largely unknown. Here, we show the detailed patterns of conformational changes and inter-subunit and -domain reorientation leading to agonist-gating and subunit-dependent competitive inhibition by providing multiple structures in distinct ligand states at 4 Å or better. The structures reveal that activation and competitive inhibition by both GluN1 and GluN2 antagonists occur by controlling the tension of the linker between the ligand-binding domain and the transmembrane ion channel of the GluN2 subunit. Our results provide detailed mechanistic insights into NMDAR pharmacology, activation, and inhibition, which are fundamental to the brain physiology.

Keywords: N-methyl-D-aspartate receptors; NMDAR antagonists; NMDARs; X-ray crystallography; channel activation and inhibition mechanisms; cryo-EM; electron cryo-microscopy; ligand-gated ion channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Binding, Competitive
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Dimerization
  • Glutamic Acid / chemistry
  • Glutamic Acid / metabolism
  • Glycine / chemistry
  • Glycine / metabolism
  • Humans
  • Ligands
  • Molecular Dynamics Simulation
  • Protein Structure, Quaternary
  • Protein Subunits / agonists
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification


  • Ligands
  • Protein Subunits
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • Glutamic Acid
  • Glycine