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

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

Author information

1
WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Watson School of Biological Sciences, Cold Spring Harbor, NY 11724, USA.
2
WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
3
WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Watson School of Biological Sciences, Cold Spring Harbor, NY 11724, USA. Electronic address: furukawa@cshl.edu.

Abstract

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

PMID:
27916457
PMCID:
PMC5182123
DOI:
10.1016/j.neuron.2016.11.006
[Indexed for MEDLINE]
Free PMC Article

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