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TitleStructural basis for antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis.
Journal, issue, pagesNat Struct Mol Biol, Year 2024
Publish dateSep 3, 2024
AuthorsHan Wang / Chun Xie / Bo Deng / Jingjun Ding / Na Li / Zengwei Kou / Mengmeng Jin / Jie He / Qinrui Wang / Han Wen / Jinbao Zhang / Qinming Zhou / Sheng Chen / Xiangjun Chen / Ti-Fei Yuan / Shujia Zhu /
PubMed AbstractAntibodies 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 ...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.
External linksNat Struct Mol Biol / PubMed:39227720
MethodsEM (single particle)
Resolution3.77 - 4.5 Å
Structure data

EMDB-36335, PDB-8jiz:
Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab5F6 in two fab bind conformation
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-36336, PDB-8jj0:
Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab5F6 in one fab bind conformation
Method: EM (single particle) / Resolution: 4.5 Å

EMDB-36337, PDB-8jj1:
Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab2G7 in two fab conformation
Method: EM (single particle) / Resolution: 3.77 Å

EMDB-36338, PDB-8jj2:
Cryo-EM structure of GluN1-2A NMDAR in complex with human Fab2G7 in one fab conformation
Method: EM (single particle) / Resolution: 4.3 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / NMDAR / autoimmune encephalitis

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