Structural scheme of GPR83 and variants with indicated findings and derived hypotheses. A) In wild type GPR83, the N-terminal domain (eNDo) is stabilized intramolecularly by side-chain interactions between specific amino acids (red broken lines). The eNDo might have a defined structural fold, which is indicated by high amino acid conservation throughout GPR83 orthologs (Figure 1). The eNDo most likely interacts with the extracellular loops (E’s 1–3) and these interactions probably maintain the basal state. B) In contrast, deletion of residues 18–35, a partial deletion, increases the inverse agonistic effect of the remaining eNDo residues on GPR83 and suppresses basal activity, by presumptively stabilizing the inactive conformation. C) Deletion of residues 35–65 of the eNDo leads to slight receptor activation, possibly due to the partial loss of intramolecular interactions with the extracellular loops. D) The GPR83 becomes highly active following removal of the entire N-terminal domain. Ctt = C-terminal tail, I = intracellular loop, E = extracellular loop.