7T0Z

Complex of GABA-A synaptic receptor with autoimmune antibody Fab175

This is a non-PDB format compatible entry.

Summary for 7T0Z

• Entry DOI: 10.2210/pdb7t0z/pdb
• EMDB information: 25583 25585
• Descriptor: Gamma-aminobutyric acid receptor subunit beta-2, 2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose, ... (11 entities in total)
• Functional Keywords: autoimmunity, encephalitis, gaba, inhibitory, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 258647.48

Authors

Noviello, C.M.,Hibbs, R.E.,Kreye, J.,Teng, J.,Pruss, H. (deposition date: 2021-11-30, release date: 2022-07-13, Last modification date: 2025-05-21)

Primary citation

Noviello, C.M.,Kreye, J.,Teng, J.,Pruss, H.,Hibbs, R.E.
Structural mechanisms of GABA A receptor autoimmune encephalitis.
Cell, 185:2469-, 2022

PubMed Abstract: Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures, and severe behavioral abnormalities. While antibodies for several neuronal targets have been identified, structural details on how they regulate function are unknown. Here we determined cryo-electron microscopy structures of antibodies derived from an encephalitis patient bound to the γ-aminobutyric acid type A (GABA) receptor. These antibodies induced severe encephalitis by directly inhibiting GABA function, resulting in nervous-system hyperexcitability. The structures reveal mechanisms of GABA inhibition and pathology. One antibody directly competes with a neurotransmitter and locks the receptor in a resting-like state. The second antibody targets the subunit interface involved in binding benzodiazepines and antagonizes diazepam potentiation. We identify key residues in these antibodies involved in specificity and affinity and confirm structure-based hypotheses for functional effects using electrophysiology. Together these studies define mechanisms of direct functional antagonism of neurotransmission underlying autoimmune encephalitis in a human patient.

PubMed: 35803245
DOI: 10.1016/j.cell.2022.06.025

Experimental method

ELECTRON MICROSCOPY (3 Å)