TY - JOUR
T1 - Mechanism of NMDA Receptor Inhibition and Activation
AU - Zhu, Shujia
AU - Stein, Richard A.
AU - Yoshioka, Craig
AU - Lee, Chia Hsueh
AU - Goehring, April
AU - McHaourab, Hassane S.
AU - Gouaux, Eric
N1 - Funding Information:
Weare grateful to Z.H. Yu, R. Huang, C. Hong (Janelia Campus), Z. Hong Zhou, and I. Atanasov (UCLA) for assistance with data collection and to R. Stites, M. Hakanson, and A. Trzynka (OHSU) for computational support. Microscopy at Oregon Health & Science University (OHSU) was performed at the Multiscale Microscopy Core (MMC) with technical support from the OHSU-FEI Living Lab, Intel, and the OHSU Center for Spatial Systems Biomedicine (OCSSB). We thank L. Vaskalis for help with illustrations, K.L. Durr, and H. Owen for proofreading; W. Lu for help with data processing; and to all the Gouaux lab members for helpful discussions. H.S.M. and R.A.S. were supported by grants U54-GM087519, and pulsed EPR instrumentation was acquired through a shared instrumentation grant S10 RR027091. This work was supported by the National Institutes of Health (5R37NS038631). E.G. is an Investigator with the Howard Hughes Medical Institute.
Funding Information:
We are grateful to Z.H. Yu, R. Huang, C. Hong (Janelia Campus), Z. Hong Zhou, and I. Atanasov (UCLA) for assistance with data collection and to R. Stites, M. Hakanson, and A. Trzynka (OHSU) for computational support. Microscopy at Oregon Health & Science University (OHSU) was performed at the Multiscale Microscopy Core (MMC) with technical support from the OHSU-FEI Living Lab, Intel, and the OHSU Center for Spatial Systems Biomedicine (OCSSB). We thank L. Vaskalis for help with illustrations, K.L. Durr, and H. Owen for proofreading; W. Lü for help with data processing; and to all the Gouaux lab members for helpful discussions. H.S.M. and R.A.S. were supported by grants U54-GM087519, and pulsed EPR instrumentation was acquired through a shared instrumentation grant S10 RR027091. This work was supported by the National Institutes of Health (5R37NS038631). E.G. is an Investigator with the Howard Hughes Medical Institute.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/4/21
Y1 - 2016/4/21
N2 - N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states and how small molecules inhibit or activate ion channel gating. Here, we report electron cryo-microscopy structures of the GluN1-GluN2B NMDA receptor in an ensemble of competitive antagonist-bound states, an agonist-bound form, and a state bound with agonists and the allosteric inhibitor Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists rupture the ligand binding domain (LBD) gating "ring," how agonists retain the ring in a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the LBD layer. These studies illuminate how the LBD gating ring is fundamental to signal transduction and gating in NMDARs.
AB - N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states and how small molecules inhibit or activate ion channel gating. Here, we report electron cryo-microscopy structures of the GluN1-GluN2B NMDA receptor in an ensemble of competitive antagonist-bound states, an agonist-bound form, and a state bound with agonists and the allosteric inhibitor Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists rupture the ligand binding domain (LBD) gating "ring," how agonists retain the ring in a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the LBD layer. These studies illuminate how the LBD gating ring is fundamental to signal transduction and gating in NMDARs.
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U2 - 10.1016/j.cell.2016.03.028
DO - 10.1016/j.cell.2016.03.028
M3 - Article
C2 - 27062927
AN - SCOPUS:84962728808
VL - 165
SP - 704
EP - 714
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -