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NMDA receptor structures reveal subunit arrangement and pore architecture.

Lee CH, Lü W, Michel JC, Goehring A, Du J, Song X, Gouaux E - Nature (2014)

Bottom Line: 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 harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a ∼twofold symmetric arrangement of ion channel pore loops.These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.

View Article: PubMed Central - PubMed

Affiliation: 1] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2].

ABSTRACT
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 Xenopus laevis 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 harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a ∼twofold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.

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Architecture, symmetry and domain organization of the GluN1/GluN2B NMDA receptora, View of the receptor complex, parallel to the membrane, with the GluN1 subunits in blue and the GluN2B subunits in orange. The ligands Ro25-6981, ACPC and t-ACBD are in space filling representation. b, View of complex rotated ~120° around overall the 2-fold axis of the receptor. The approximate position of the overall 2-fold axis is shown by a vertical gray bar in the center of the ATD layer. Structure 2 is shown.
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Figure 1: Architecture, symmetry and domain organization of the GluN1/GluN2B NMDA receptora, View of the receptor complex, parallel to the membrane, with the GluN1 subunits in blue and the GluN2B subunits in orange. The ligands Ro25-6981, ACPC and t-ACBD are in space filling representation. b, View of complex rotated ~120° around overall the 2-fold axis of the receptor. The approximate position of the overall 2-fold axis is shown by a vertical gray bar in the center of the ATD layer. Structure 2 is shown.

Mentions: The structure of the GluN1/GluN2B NMDA receptor resembles that of a mushroom with a height of ~150 Å and widths of ~125 × 115 Å (Fig. 1a, b; ,Supplementary Video 1). Endowed with an overall 2-fold axis of symmetry, reminiscent of the intact GluA2 AMPA receptor architecture and symmetry28, the receptor domains are organized into three layers with the ATD layer at the ‘top’, the LBD layer in the ‘middle’ and the TMD layer at the ‘bottom’. By contrast with the AMPA receptor, the extracellular layers are more compact, with the ATD layer adopting an entirely different structure, interdigitated within the crevices of the LBD layer. The LBD layer caps the extracellular end of the transmembrane domain, with loops from the GluN2B LBDs drooping toward the extracellular leaflet of the membrane bilayer (Fig. 1a). The TMD hews to an AMPA-like topology and arrangement of helices28, yet with electron density for the M2 segments and pore loops in Structure 2, allowing us to define the structure of nearly the entire ion channel pore. Structure 1 and Structure 2 are similar, nevertheless, with an overall rmsd on main chain atoms of 0.6 Å. Here we primarily use Structure 1 to discuss the ATDs, LBDs and LBD to TMD linkages and Structure 2 to describe the TMD.


NMDA receptor structures reveal subunit arrangement and pore architecture.

Lee CH, Lü W, Michel JC, Goehring A, Du J, Song X, Gouaux E - Nature (2014)

Architecture, symmetry and domain organization of the GluN1/GluN2B NMDA receptora, View of the receptor complex, parallel to the membrane, with the GluN1 subunits in blue and the GluN2B subunits in orange. The ligands Ro25-6981, ACPC and t-ACBD are in space filling representation. b, View of complex rotated ~120° around overall the 2-fold axis of the receptor. The approximate position of the overall 2-fold axis is shown by a vertical gray bar in the center of the ATD layer. Structure 2 is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4263351&req=5

Figure 1: Architecture, symmetry and domain organization of the GluN1/GluN2B NMDA receptora, View of the receptor complex, parallel to the membrane, with the GluN1 subunits in blue and the GluN2B subunits in orange. The ligands Ro25-6981, ACPC and t-ACBD are in space filling representation. b, View of complex rotated ~120° around overall the 2-fold axis of the receptor. The approximate position of the overall 2-fold axis is shown by a vertical gray bar in the center of the ATD layer. Structure 2 is shown.
Mentions: The structure of the GluN1/GluN2B NMDA receptor resembles that of a mushroom with a height of ~150 Å and widths of ~125 × 115 Å (Fig. 1a, b; ,Supplementary Video 1). Endowed with an overall 2-fold axis of symmetry, reminiscent of the intact GluA2 AMPA receptor architecture and symmetry28, the receptor domains are organized into three layers with the ATD layer at the ‘top’, the LBD layer in the ‘middle’ and the TMD layer at the ‘bottom’. By contrast with the AMPA receptor, the extracellular layers are more compact, with the ATD layer adopting an entirely different structure, interdigitated within the crevices of the LBD layer. The LBD layer caps the extracellular end of the transmembrane domain, with loops from the GluN2B LBDs drooping toward the extracellular leaflet of the membrane bilayer (Fig. 1a). The TMD hews to an AMPA-like topology and arrangement of helices28, yet with electron density for the M2 segments and pore loops in Structure 2, allowing us to define the structure of nearly the entire ion channel pore. Structure 1 and Structure 2 are similar, nevertheless, with an overall rmsd on main chain atoms of 0.6 Å. Here we primarily use Structure 1 to discuss the ATDs, LBDs and LBD to TMD linkages and Structure 2 to describe the TMD.

Bottom Line: 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 harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a ∼twofold symmetric arrangement of ion channel pore loops.These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.

View Article: PubMed Central - PubMed

Affiliation: 1] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2].

ABSTRACT
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 Xenopus laevis 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 harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a ∼twofold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.

Show MeSH