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

Romero-Hernandez, Annabel, Simorowski, Noriko, Karakas, Erkan, Furukawa, Hiro (2016) Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain. Neuron, 92 (6). pp. 1324-1336. ISSN 0896-6273

URL: https://www.ncbi.nlm.nih.gov/pubmed/27916457
DOI: 10.1016/j.neuron.2016.11.006

Abstract

Summary 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.

Item Type: Paper
Uncontrolled Keywords: ionotropic glutamate receptors N-methyl-D-aspartate receptors crystal structure subtype specificity zinc inhibition amino-terminal domain ifenprodil
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > ionotropic glutamate receptor
structural biology
Investigative techniques and equipment > x ray crystallography
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Watson School > Publications
Depositing User: Matt Covey
Date Deposited: 09 Dec 2016 21:59
Last Modified: 07 Sep 2017 15:34
PMCID: PMC5182123
Related URLs:
Dataset ID:
URI: http://repository.cshl.edu/id/eprint/33920

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