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

Romero-Hernandez A, Simorowski N, Karakas E, Furukawa H
Neuron. 2016 92 (6): 1324-1336

PMID: 27916457 · PMCID: PMC5182123 · DOI:10.1016/j.neuron.2016.11.006

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.

Copyright © 2016 Elsevier Inc. All rights reserved.

MeSH Terms (13)

2-Hydroxyphenethylamine Animals Binding Sites Blotting, Western Crystallography Hydrogen Bonding Piperidines Protein Structure, Quaternary Receptors, N-Methyl-D-Aspartate Sf9 Cells Spodoptera Xenopus laevis Zinc

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