@article{86b770f2093e413bbc3a3c178631a45f,
title = "Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor",
abstract = "N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to schizophrenia. Zinc and pH are physiological allosteric modulators of NMDARs, with GluN2A-containing receptors inhibited by nanomolar concentrations of divalent zinc and by excursions to low pH. Despite the widespread importance of zinc and proton modulation of NMDARs, the molecular mechanism by which these ions modulate receptor activity has proven elusive. Here, we use cryoelectron microscopy to elucidate the structure of the GluN1/GluN2A NMDAR in a large ensemble of conformations under a range of physiologically relevant zinc and proton concentrations. We show how zinc binding to the amino terminal domain elicits structural changes that are transduced though the ligand-binding domain and result in constriction of the ion channel gate. Cryo-EM structures of the full-length GluN1/GluN2A diheteromeric receptor across a range of physiologically relevant zinc and proton concentrations illustrates how zinc binding elicits structural changes that result in constriction of the ion channel gate.",
keywords = "allosteric modulation, glutamate receptor, ligand-gated ion channel, neurotransmitter receptor, proton-inhibition, structural biology, synapse, zinc-inhibition",
author = "Farzad Jalali-Yazdi and Sandipan Chowdhury and Craig Yoshioka and Eric Gouaux",
note = "Funding Information: We thank Z.H. Yu, H.T. Chou, and R. Huong from Janelia Research Campus for assistance with data collection. Electron microscopy was performed at Oregon Health and Science University (OHSU) at the Multiscale Microscopy Core (MMC) with technical support from the Oregon Health and Science University (OHSU)-FEI Living Lab and the OHSU Center for Spatial Systems Biomedicine (OCSSB). We thank Richard W. Roberts, Terry T. Takahashi, and Jasmine M. Corbin for providing us with the sequence of the DNSA tag. Elemental analysis to quantitate background zinc contamination was performed in the OHSU Elemental Analysis Core. We thank all of the members of the Gouaux, Baconguis, and Whorton labs for helpful discussions. We thank A.J. Romero and L. Vaskalis for help with the illustrations, and we thank H. Owen, N. Yoder, and V. Navratna for proofreading. F.J.Y. is supported by the NIH ( 1F32MH115595 ). S.C. is supported by the Jane Coffin Childs Fund ( 61-1591 ). This work was supported by the NIH ( R01NS038631 ). E.G. is an investigator with the Howard Hughes Medical Institute. Funding Information: We thank Z.H. Yu, H.T. Chou, and R. Huong from Janelia Research Campus for assistance with data collection. Electron microscopy was performed at Oregon Health and Science University (OHSU) at the Multiscale Microscopy Core (MMC) with technical support from the Oregon Health and Science University (OHSU)-FEI Living Lab and the OHSU Center for Spatial Systems Biomedicine (OCSSB). We thank Richard W. Roberts, Terry T. Takahashi, and Jasmine M. Corbin for providing us with the sequence of the DNSA tag. Elemental analysis to quantitate background zinc contamination was performed in the OHSU Elemental Analysis Core. We thank all of the members of the Gouaux, Baconguis, and Whorton labs for helpful discussions. We thank A.J. Romero and L. Vaskalis for help with the illustrations, and we thank H. Owen, N. Yoder, and V. Navratna for proofreading. F.J.Y. is supported by the NIH (1F32MH115595). S.C. is supported by the Jane Coffin Childs Fund (61-1591). This work was supported by the NIH (R01NS038631). E.G. is an investigator with the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = nov,
day = "29",
doi = "10.1016/j.cell.2018.10.043",
language = "English (US)",
volume = "175",
pages = "1520--1532.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}