Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation

Wei Lü, Juan Du, April Goehring, Eric Gouaux

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ion channels assembled as diheteromeric or triheteromeric complexes. Here, we report structures of the triheteromeric GluN1/GluN2A/GluN2B receptor in the absence or presence of the GluN2Bspecific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt "closed" and "open" clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold-related GluN1 subunits further reflect receptor asymmetry. The triheteromeric NMDAR structures provide the first view of the most common NMDA receptor assembly and show how incorporation of two different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity.

Original languageEnglish (US)
Article numbereaal3729
JournalScience
Volume355
Issue number6331
DOIs
StatePublished - Mar 24 2017

Fingerprint

N-Methyl-D-Aspartate Receptors
Ion Channel Gating
Ion Channels
Electron Microscopy

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation. / Lü, Wei; Du, Juan; Goehring, April; Gouaux, Eric.

In: Science, Vol. 355, No. 6331, eaal3729, 24.03.2017.

Research output: Contribution to journalArticle

Lü, Wei ; Du, Juan ; Goehring, April ; Gouaux, Eric. / Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation. In: Science. 2017 ; Vol. 355, No. 6331.
@article{de9daa98597146298dd34c1cc0d16646,
title = "Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation",
abstract = "N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ion channels assembled as diheteromeric or triheteromeric complexes. Here, we report structures of the triheteromeric GluN1/GluN2A/GluN2B receptor in the absence or presence of the GluN2Bspecific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt {"}closed{"} and {"}open{"} clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold-related GluN1 subunits further reflect receptor asymmetry. The triheteromeric NMDAR structures provide the first view of the most common NMDA receptor assembly and show how incorporation of two different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity.",
author = "Wei L{\"u} and Juan Du and April Goehring and Eric Gouaux",
year = "2017",
month = "3",
day = "24",
doi = "10.1126/science.aal3729",
language = "English (US)",
volume = "355",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6331",

}

TY - JOUR

T1 - Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation

AU - Lü, Wei

AU - Du, Juan

AU - Goehring, April

AU - Gouaux, Eric

PY - 2017/3/24

Y1 - 2017/3/24

N2 - N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ion channels assembled as diheteromeric or triheteromeric complexes. Here, we report structures of the triheteromeric GluN1/GluN2A/GluN2B receptor in the absence or presence of the GluN2Bspecific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt "closed" and "open" clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold-related GluN1 subunits further reflect receptor asymmetry. The triheteromeric NMDAR structures provide the first view of the most common NMDA receptor assembly and show how incorporation of two different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity.

AB - N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ion channels assembled as diheteromeric or triheteromeric complexes. Here, we report structures of the triheteromeric GluN1/GluN2A/GluN2B receptor in the absence or presence of the GluN2Bspecific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt "closed" and "open" clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold-related GluN1 subunits further reflect receptor asymmetry. The triheteromeric NMDAR structures provide the first view of the most common NMDA receptor assembly and show how incorporation of two different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity.

UR - http://www.scopus.com/inward/record.url?scp=85013781123&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85013781123&partnerID=8YFLogxK

U2 - 10.1126/science.aal3729

DO - 10.1126/science.aal3729

M3 - Article

C2 - 28232581

AN - SCOPUS:85013781123

VL - 355

JO - Science

JF - Science

SN - 0036-8075

IS - 6331

M1 - eaal3729

ER -