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
N1 - Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS038631 (to E.G.). E.G. is an investigator with the Howard Hughes Medical Institute. The cryo-EM density maps and coordinates of non-Ro-bound and Ro-bound triNMDARs in complex with Fab 11D1 have been deposited in the Electron Microscopy Data Bank (EMDB) under accession numbers EMD-8579 and EMD-8581 and in the Research Collaboratory for Structural Bioinformatics Protein Data Bank under accession codes 5UOW and 5UP2, respectively. The cryo-EM density maps of non-Ro-bound triNMDAR-G610 in complex with Fab 11D1 and Ro-bound triNMDAR have been deposited in the EMDB under accession numbers EMD-8580 and EMD-8583.
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.
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U2 - 10.1126/science.aal3729
DO - 10.1126/science.aal3729
M3 - Article
C2 - 28232581
AN - SCOPUS:85013781123
SN - 0036-8075
VL - 355
JO - Science
JF - Science
IS - 6331
M1 - eaal3729
ER -