8VVH

rat GluN1a-2B Fab 003-102 local refinement

Summary for 8VVH

• Entry DOI: 10.2210/pdb8vvh/pdb
• EMDB information: 43559
• Descriptor: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2B, 003-102 Heavy, ... (4 entities in total)
• Functional Keywords: channel, heterotetramer, receptor, antibody, membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 4
• Total formula weight: 105515.77

Authors

Michalski, K.,Furukawa, H. (deposition date: 2024-01-31, release date: 2024-09-11, Last modification date: 2024-10-16)

Primary citation

Michalski, K.,Abdulla, T.,Kleeman, S.,Schmidl, L.,Gomez, R.,Simorowski, N.,Vallese, F.,Pruss, H.,Heckmann, M.,Geis, C.,Furukawa, H.
Structural and functional mechanisms of anti-NMDAR autoimmune encephalitis.
Nat.Struct.Mol.Biol., 2024

PubMed Abstract: Autoantibodies against neuronal membrane proteins can manifest in autoimmune encephalitis, inducing seizures, cognitive dysfunction and psychosis. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most dominant autoimmune encephalitis; however, insights into how autoantibodies recognize and alter receptor functions remain limited. Here we determined structures of human and rat NMDARs bound to three distinct patient-derived antibodies using single-particle electron cryo-microscopy. These antibodies bind different regions within the amino-terminal domain of the GluN1 subunit. Through electrophysiology, we show that all three autoantibodies acutely and directly reduced NMDAR channel functions in primary neurons. Antibodies show different stoichiometry of binding and antibody-receptor complex formation, which in one antibody, 003-102, also results in reduced synaptic localization of NMDARs. These studies demonstrate mechanisms of diverse epitope recognition and direct channel regulation of anti-NMDAR autoantibodies underlying autoimmune encephalitis.

PubMed: 39227719
DOI: 10.1038/s41594-024-01386-4

Experimental method

ELECTRON MICROSCOPY (3.95 Å)