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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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Comparison of LBD layers and LBD-TMD linkers between the NMDA receptor and the GluA2 receptor structuresa, View from the extracellular side of the membrane of the connections between the TMD and LBD domains of the GluN1/GluN2B structure and of the GluA2 structure (PDB 3KG2), showing the relative rotation of GluA2 layer by ~35°. The S2 segment resides within the LBD. The LBD-M3 linkers are highlighted. b, The LBD-M1 linkers are highlighted. c, The LBD-M4 linkers are highlighted. Shown in all panels are structures derived from Data set 1/Structure 1.
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Figure 14: Comparison of LBD layers and LBD-TMD linkers between the NMDA receptor and the GluA2 receptor structuresa, View from the extracellular side of the membrane of the connections between the TMD and LBD domains of the GluN1/GluN2B structure and of the GluA2 structure (PDB 3KG2), showing the relative rotation of GluA2 layer by ~35°. The S2 segment resides within the LBD. The LBD-M3 linkers are highlighted. b, The LBD-M1 linkers are highlighted. c, The LBD-M4 linkers are highlighted. Shown in all panels are structures derived from Data set 1/Structure 1.

Mentions: The coupling of the LBD to the TMD is similar, in principle, to the AMPA receptor28, with the crucial M3 connections to the LBDs proximal or distal to the overall 2-fold axis for the GluN1 A/C subunits or the GluN2B B/D subunits, respectively (Extended Data Fig. 8). However, the relative orientation of the NMDA receptor TMD with respect to the LBD is distinct from the GluA2 receptor. Specifically, the LBD layer of the NMDA receptor is rotated by ~35° around an axis that is approximately coincident with the overall 2-fold axis of the receptor. At this juncture we do not know if this difference is due to inherent differences between NMDA and AMPA receptors or because this specific NMDA receptor complex is trapped in an ATD antagonist-bound, LBD partial-agonist bound, closed-blocked state.


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)

Comparison of LBD layers and LBD-TMD linkers between the NMDA receptor and the GluA2 receptor structuresa, View from the extracellular side of the membrane of the connections between the TMD and LBD domains of the GluN1/GluN2B structure and of the GluA2 structure (PDB 3KG2), showing the relative rotation of GluA2 layer by ~35°. The S2 segment resides within the LBD. The LBD-M3 linkers are highlighted. b, The LBD-M1 linkers are highlighted. c, The LBD-M4 linkers are highlighted. Shown in all panels are structures derived from Data set 1/Structure 1.
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Related In: Results  -  Collection

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Figure 14: Comparison of LBD layers and LBD-TMD linkers between the NMDA receptor and the GluA2 receptor structuresa, View from the extracellular side of the membrane of the connections between the TMD and LBD domains of the GluN1/GluN2B structure and of the GluA2 structure (PDB 3KG2), showing the relative rotation of GluA2 layer by ~35°. The S2 segment resides within the LBD. The LBD-M3 linkers are highlighted. b, The LBD-M1 linkers are highlighted. c, The LBD-M4 linkers are highlighted. Shown in all panels are structures derived from Data set 1/Structure 1.
Mentions: The coupling of the LBD to the TMD is similar, in principle, to the AMPA receptor28, with the crucial M3 connections to the LBDs proximal or distal to the overall 2-fold axis for the GluN1 A/C subunits or the GluN2B B/D subunits, respectively (Extended Data Fig. 8). However, the relative orientation of the NMDA receptor TMD with respect to the LBD is distinct from the GluA2 receptor. Specifically, the LBD layer of the NMDA receptor is rotated by ~35° around an axis that is approximately coincident with the overall 2-fold axis of the receptor. At this juncture we do not know if this difference is due to inherent differences between NMDA and AMPA receptors or because this specific NMDA receptor complex is trapped in an ATD antagonist-bound, LBD partial-agonist bound, closed-blocked state.

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