NMDA receptor structures reveal subunit arrangement and pore architecture

NMDA receptor structures reveal subunit arrangement and pore architecture

N-methyl-d-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the...

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Main Authors: Lee, Chia-Hsueh, Lü, Wei, Michel, Jennifer Carlisle, Goehring, April, Du, Juan, Song, Xianqiang, Gouaux, Eric
Format: Online
Language:English
Published: 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263351/
id pubmed-4263351
recordtype oai_dc
spelling pubmed-42633512015-01-10 NMDA receptor structures reveal subunit arrangement and pore architecture Lee, Chia-Hsueh Lü, Wei Michel, Jennifer Carlisle Goehring, April Du, Juan Song, Xianqiang Gouaux, Eric Article N-methyl-d-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the development and function of the brain, a molecular structure of an intact receptor has remained elusive. Here we present x-ray crystal structures of the GluN1/GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino terminal and ligand binding domains. The transmembrane domains harbor a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a ~2-fold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors. 2014-06-22 2014-07-10 /pmc/articles/PMC4263351/ /pubmed/25008524 http://dx.doi.org/10.1038/nature13548 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Lee, Chia-Hsueh
Lü, Wei
Michel, Jennifer Carlisle
Goehring, April
Du, Juan
Song, Xianqiang
Gouaux, Eric
spellingShingle Lee, Chia-Hsueh
Lü, Wei
Michel, Jennifer Carlisle
Goehring, April
Du, Juan
Song, Xianqiang
Gouaux, Eric
NMDA receptor structures reveal subunit arrangement and pore architecture
author_facet Lee, Chia-Hsueh
Lü, Wei
Michel, Jennifer Carlisle
Goehring, April
Du, Juan
Song, Xianqiang
Gouaux, Eric
author_sort Lee, Chia-Hsueh
title NMDA receptor structures reveal subunit arrangement and pore architecture
title_short NMDA receptor structures reveal subunit arrangement and pore architecture
title_full NMDA receptor structures reveal subunit arrangement and pore architecture
title_fullStr NMDA receptor structures reveal subunit arrangement and pore architecture
title_full_unstemmed NMDA receptor structures reveal subunit arrangement and pore architecture
title_sort nmda receptor structures reveal subunit arrangement and pore architecture
description N-methyl-d-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the development and function of the brain, a molecular structure of an intact receptor has remained elusive. Here we present x-ray crystal structures of the GluN1/GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino terminal and ligand binding domains. The transmembrane domains harbor a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a ~2-fold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263351/
_version_ 1613166516792983552

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