TY - JOUR
T1 - NMDA receptor structures reveal subunit arrangement and pore architecture
AU - Lee, Chia Hsueh
AU - Lü, Wei
AU - Michel, Jennifer Carlisle
AU - Goehring, April
AU - Du, Juan
AU - Song, Xianqiang
AU - Gouaux, Eric
N1 - Funding Information:
Acknowledgements All members of the Gouaux laboratory are gratefully acknowledged for their support and assistance, especially L. Chen, K. Duerr and K. Wang. We thank L. Vaskalis for assistance with the figures, G. Westbrook and C. Jahr for comments on the manuscript, H. Owen for proofreading and I. Baconguis for making the animation. E.G. acknowledges the generous support of R. LaCroute, B. LaCroute and J. LaCroute. This work was also supported by an Oregon Brain Institute Graduate Student Fellowship (C.H.L.), the NIH (E.G.) and the Vollum Institute (E.G.). E.G. is an investigator of the Howard Hughes Medical Institute.
PY - 2014
Y1 - 2014
N2 - 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 â ̂1/4twofold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.
AB - 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 â ̂1/4twofold 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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U2 - 10.1038/nature13548
DO - 10.1038/nature13548
M3 - Article
C2 - 25008524
AN - SCOPUS:84904199124
SN - 0028-0836
VL - 511
SP - 191
EP - 197
JO - Nature
JF - Nature
IS - 7508
ER -