8JIZ

Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab5F6 in two fab bind conformation

Summary for 8JIZ

• Entry DOI: 10.2210/pdb8jiz/pdb
• EMDB information: 36335
• Descriptor: Glutamate receptor ionotropic, NMDA 2A, Glutamate receptor ionotropic, NMDA 1, Fab5F6 Heavy Chain, ... (6 entities in total)
• Functional Keywords: nmdar, autoimmune encephalitis, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 489768.21

Authors

Wang, H.,Zhu, S. (deposition date: 2023-05-29, release date: 2024-06-05, Last modification date: 2024-10-30)

Primary citation

Wang, H.,Xie, C.,Deng, B.,Ding, J.,Li, N.,Kou, Z.,Jin, M.,He, J.,Wang, Q.,Wen, H.,Zhang, J.,Zhou, Q.,Chen, S.,Chen, X.,Yuan, T.F.,Zhu, S.
Structural basis for antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis.
Nat.Struct.Mol.Biol., 2024

PubMed Abstract: Antibodies against N-methyl-D-aspartate receptors (NMDARs) are most frequently detected in persons with autoimmune encephalitis (AE) and used as diagnostic biomarkers. Elucidating the structural basis of monoclonal antibody (mAb) binding to NMDARs would facilitate the development of targeted therapy for AE. Here, we reconstructed nanodiscs containing green fluorescent protein-fused NMDARs to label and sort individual immune B cells from persons with AE and further cloned and identified mAbs against NMDARs. This allowed cryo-electron microscopy analysis of NMDAR-Fab complexes, revealing that autoantibodies bind to the R1 lobe of the N-terminal domain of the GluN1 subunit. Small-angle X-ray scattering studies demonstrated NMDAR-mAb stoichiometry of 2:1 or 1:2, structurally suitable for mAb-induced clustering and endocytosis of NMDARs. Importantly, these mAbs reduced the surface NMDARs and NMDAR-mediated currents, without tonically affecting NMDAR channel gating. These structural and functional findings imply that the design of neutralizing antibody binding to the R1 lobe of NMDARs represents a potential therapy for AE treatment.

PubMed: 39227720
DOI: 10.1038/s41594-024-01387-3

Experimental method

ELECTRON MICROSCOPY (3.8 Å)