Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors

Han Wang; Shiyun Lv; David Stroebel; Jinbao Zhang; Yijie Pan; Xuejing Huang; Xing Zhang; Pierre Paoletti; Shujia Zhu

doi:10.1016/j.neuron.2021.05.031

Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors

Neuron. 2021 Aug 4;109(15):2443-2456.e5. doi: 10.1016/j.neuron.2021.05.031. Epub 2021 Jun 28.

Authors

Han Wang¹, Shiyun Lv¹, David Stroebel², Jinbao Zhang³, Yijie Pan³, Xuejing Huang³, Xing Zhang⁴, Pierre Paoletti², Shujia Zhu⁵

Affiliations

¹ Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM, Paris, France.
³ Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
⁴ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Center of Cryo Electron Microscopy, Zhejiang University School of Medicine, Hangzhou, China.
⁵ Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China. Electronic address: shujiazhu@ion.ac.cn.

PMID: 34186027
DOI: 10.1016/j.neuron.2021.05.031

Abstract

N-methyl-D-aspartate (NMDA) receptors are glutamate-gated calcium-permeable ion channels that are widely implicated in synaptic transmission and plasticity. Here, we report a gallery of cryo-electron microscopy (cryo-EM) structures of the human GluN1-GluN2A NMDA receptor at an overall resolution of 4 Å in complex with distinct ligands or modulators. In the full-length context of GluN1-GluN2A receptors, we visualize the competitive antagonists bound to the ligand-binding domains (LBDs) of GluN1 and GluN2A subunits, respectively. We reveal that the binding of positive allosteric modulator shortens the distance between LBDs and the transmembrane domain (TMD), which further stretches the opening of the gate. In addition, we unexpectedly visualize the binding cavity of the "foot-in-the-door" blocker 9-aminoacridine within the LBD-TMD linker region, differing from the conventional "trapping" blocker binding site at the vestibule within the TMD. Our study provides molecular insights into the crosstalk between LBDs and TMD during channel activation, inhibition, and allosteric transition.

Keywords: 9-aminoacrodine; NMDA receptor; allosteric modulation; gating transition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Cryoelectron Microscopy
Humans
Models, Molecular*
Nerve Tissue Proteins / metabolism*
Nerve Tissue Proteins / ultrastructure*
Protein Domains / physiology
Receptors, N-Methyl-D-Aspartate / metabolism*
Receptors, N-Methyl-D-Aspartate / ultrastructure*

Substances

GRIN1 protein, human
Nerve Tissue Proteins
Receptors, N-Methyl-D-Aspartate
N-methyl D-aspartate receptor subtype 2A

Grants and funding

R00 MH118423/MH/NIMH NIH HHS/United States