Anti-N-Methyl D-aspartate receptor encephalitis is an autoimmune disease in which autoantibodies are produced against extracellular regions of the N-Methyl D-aspartate receptor (NMDAR). In this study, we used resin-bound peptides equipped with a base labile linker to map the epitope of a monoclonal NMDAR antibody against the NMDAR NR1 subunit. The antigenicity of the synthesized resin-bound peptides was determined by enzyme-linked immunosorbent assay. Distinct reactivity was found to two extracellular overlapping peptides (amino acids, 658-687). Using N- and C-terminally truncated resin-bound peptides, the minimum functional epitope was identified as the NPSDK sequence. The peptide sequence RNPSDK (amino acids, 673-678) was identified as the complete epitope, which was found to be located in the extracellular S2 domain of the NR1 subunit. Especially, the N-terminal arginine residue was found to be essential for reactivity, whereas the remaining amino acids could be replaced with amino acids of similar side-chain functionality, indicating the importance of backbone interaction in antibody reactivity.
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