Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain

Neuron. 2016 Dec 21;92(6):1324-1336. doi: 10.1016/j.neuron.2016.11.006. Epub 2016 Dec 1.


Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure. Here we show the first crystal structures of the heterodimeric GluN1-GluN2A ATD, which provide the complete map of the high-affinity zinc-binding site and reveal distinctive features from the ATD of the GluN1-GluN2B subtype. Perturbation of hydrogen bond networks at the hinge of the GluN2A bi-lobe structure affects both zinc inhibition and open probability, supporting the general model in which the bi-lobe motion in ATD regulates the channel activity in NMDA receptors.

Keywords: N-methyl-D-aspartate receptors; amino-terminal domain; crystal structure; ifenprodil; ionotropic glutamate receptors; subtype specificity; zinc inhibition.

MeSH terms

  • 2-Hydroxyphenethylamine / metabolism
  • Animals
  • Binding Sites
  • Blotting, Western
  • Crystallography
  • Hydrogen Bonding
  • Piperidines / pharmacology
  • Protein Structure, Quaternary
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Sf9 Cells
  • Spodoptera
  • Xenopus laevis
  • Zinc / metabolism*
  • Zinc / pharmacology


  • NR2B NMDA receptor
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • 2-Hydroxyphenethylamine
  • Zinc
  • ifenprodil
  • N-methyl D-aspartate receptor subtype 2A