7t0z
Complex of GABA-A synaptic receptor with autoimmune antibody Fab175
Structural highlights
FunctionGBRB2_HUMAN Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.[1] [2] Publication Abstract from PubMedAutoantibodies 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 gamma-aminobutyric acid type A (GABA(A)) receptor. These antibodies induced severe encephalitis by directly inhibiting GABA(A) function, resulting in nervous-system hyperexcitability. The structures reveal mechanisms of GABA(A) 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. Structural mechanisms of GABA(A) receptor autoimmune encephalitis.,Noviello CM, Kreye J, Teng J, Pruss H, Hibbs RE Cell. 2022 Jul 7;185(14):2469-2477.e13. doi: 10.1016/j.cell.2022.06.025. PMID:35803245[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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