Romero-Hernandez, Annabel, Simorowski, Noriko, Karakas, Erkan, Furukawa, Hiro (December 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 (Public Dataset)
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 School of Biological Sciences > Publications |
| Depositing User: | Matt Covey |
| Date: | 21 December 2016 |
| Date Deposited: | 09 Dec 2016 21:59 |
| Last Modified: | 07 Sep 2017 15:34 |
| PMCID: | PMC5182123 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/33920 |
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