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| Title | Cryo-EM of autoantibody-bound NMDA receptors reveals antigenic hotspots in an active immunization model of anti-NMDAR encephalitis. |
|---|---|
| Journal, issue, pages | Sci Adv, Vol. 12, Issue 3, Page eaeb4249, Year 2026 |
| Publish date | Jan 16, 2026 |
Authors | Junhoe Kim / Farzad Jalali-Yazdi / Brian E Jones / Gary L Westbrook / Eric Gouaux / ![]() |
| PubMed Abstract | Autoantibodies targeting synaptic membrane proteins are associated with autoimmune encephalitis manifested by seizures, psychosis, and memory dysfunction. Anti--methyl-d-aspartate receptor (NMDAR) ...Autoantibodies targeting synaptic membrane proteins are associated with autoimmune encephalitis manifested by seizures, psychosis, and memory dysfunction. Anti--methyl-d-aspartate receptor (NMDAR) encephalitis, a prototype of these autoimmune synaptic disorders, is unexpectedly common. Unfortunately, how the native repertoire of anti-NMDAR autoantibodies recognizes NMDARs and the precise locations of antigenic epitopes remain poorly understood. Here, we used an active immunization model that closely mimics the human disease to immunize adult mice with intact GluN1/GluN2A receptors, resulting in fulminant autoimmune encephalitis. Serum was collected at 6 weeks postimmunization for single-particle cryo-electron microscopy of GluN1/GluN2A receptors complexed with purified polyclonal anti-NMDAR autoantibody fragments. Native autoantibodies recognized two distinct binding sites on the GluN1 amino-terminal domain, which we confirmed using monoclonal antibodies bound to native NMDARs purified from mouse brain. Structural analysis of autoantibody-bound NMDAR complexes identified antigenic hotspots within the GluN1 amino-terminal domain. These hotspots provide potential targets for therapeutic intervention. |
External links | Sci Adv / PubMed:41533802 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.76 - 6.56 Å |
| Structure data | EMDB-72076, PDB-9pzq: EMDB-72077, PDB-9pzr: EMDB-72078, PDB-9pzs: ![]() EMDB-72079: Native GluN1/GluN2A/GluNx in complex with 5F11 and 3D2 Fabs (class 2), glycine and glutamate-bound state EMDB-72080, PDB-9pzt: EMDB-72081, PDB-9pzu: ![]() EMDB-72082: Native GluN1/GluNx in complex with 5F11 Fab (class 5), glycine and glutamate-bound state EMDB-72083, PDB-9pzv: EMDB-72084, PDB-9pzw: EMDB-72085, PDB-9pzx: |
| Chemicals | ![]() ChemComp-NAG: ![]() ChemComp-GLY: ![]() ChemComp-GLU: |
| Source |
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Keywords | TRANSPORT PROTEIN / ligand-gated ion channel / NMDA / antibody / complex / native |
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