Receptors for the major excitatory neurotransmitter glutamate include metabotropic (G protein-coupled) and ionotropic (glutamate-gated ion channel) types. These receptors have large, presumably extracellular, amino-terminal domains. Sensitive sequence analysis techniques indicate that the metabotropic receptor extracellular domain is similar to bacterial periplasmic amino acid binding proteins. A structural model built using the observed similarity predicts a ligand-binding site, and mutants with conservative amino acid substitutions at this site are shown to have reduced ligand affinity. The metabotropic receptor extracellular domain is a member of a family of structural domains linked to a variety of receptor types, including ionotropic glutamate receptors.