Human chorionic gonadotropin (hCG) is a member of the glycoprotein hormone family. It is composed of an alpha and a beta subunit, the latter being closely homologous to that of human luteinizing hormone (hLH). HCG and hLH bind to the same receptor. The molecular mass of hCG is 38 kD, up to 30% of which is contributed by the carbohydrate moieties linked to each of the two subunits. Structure-function relationship studies have indicated that both subunits interact with the receptor and that altogether four different peptide domains (two on each subunit) are responsible for high-affinity receptor binding. The carbohydrate units are responsible for expression of agonist activity: deglycosylated hCG (degly-hCG) is unable to induce a biological response (cAMP increase), despite high-affinity binding. We have previously mapped the antigenic surface of hCG and described 14 different epitopes that can be recognized by specific monoclonal antibodies (MCA), i.e. five epitopes on the alpha subunit, five on the beta subunit and four epitopes which are formed through association of the two subunits (conformational or alpha beta epitopes). The number and topography of epitopes was found to be the same on degly-hCG. This framework of immunological coordinates was then applied to probe the orientation of hCG, as well as that of the competitive antagonist degly-hCG in their receptor-bound states. With a receptor-hormone-125I-MCA sandwich approach we found that while hCG still presented two of the 14 epitopes, i.e. beta 3 and beta 5, no epitope was accessible on receptor-bound degly-hCG. This differential pattern thus correlates with the signal transduction-competence of the respective ligand. Overall, these data indicate that most of the surface of hCG is masked by moieties of the receptor. Accordingly, that moiety must itself be folded in a way that it provides a large contact surface. No portion other than the 341-residue long extracellular domain would seem capable of doing that. Computer-assisted secondary structure predictions support this view. This domain is the novel feature that distinguishes glycoprotein-hormone receptors from the other members of the G protein-coupled receptor superfamily.