Figure 7.

Details of thyroid-stimulating hormone receptor (TSHR) structure and activation. This complex model visualizes important determinants and aspects of the TSHR activation mechanism. The hinge region links the LRRD with the serpentine domain and both parts harbor determinants for hormone binding. Ligand-binding triggers conformational changes at a convergent center between the LRRD and hinge region, thereby an inhibitory impact of the extracellular part on the receptor gets abrogated and an “intramolecular agonistic unit” or “tethered internal agonist” close to the transmembrane domain 1 becomes activated (violet surface). This extracellular signal induction is conveyed via structural rearrangements of the transmembrane-spanning helices toward the intracellular side. Several amino acids of high structural–functional relevance are involved in receptor activation (orange sticks) by maintaining specific activity-related conformations. They are localized at distinct spatial regions inside the TSHR, and they are interrelated with each other. The resulting active receptor conformation opens a spatial crevice for binding of intracellular interaction partners (Figures 6 and 8). Notably, the TSHR is characterized by specificities in the structural details such as a regular conformation of TMH5 compared to most other G-protein-coupled receptors (GPCRs), having an alanine instead of a proline at the 5×50 position, respectively. Moreover, the TSHR like all other glycoprotein hormone receptors (GPHRs) has a methionine at position 6×47 in TMH6, where usually a tryptophan is located in most class A GPCRs. In addition, it has been shown several times (48, 110, 177) that the known allosteric-binding sites for small drug-like molecules acting on GPHRs are located between the transmembrane helices close to the extracellular loops, which is shown here exemplarily by a partial surface-pocket representation and a bound synthetic antagonist.