Abstract
The thyrotropin receptor (TSHR), the lutropin- (LHR), and the follicotropin receptor
(FSHR) belong to glycoprotein hormone receptors (GPHR), a subgroup of the class A
G-protein coupled receptors. In this review, the unique features of GPHR have been
taken into account for their pharmacological interventions: i) The respective hormone
and stimulating or blocking antibodies are binding on the large ectodomain that is
ii) via a hinge region, containing iii) an internal tethered agonist linked to the
transmembrane domain. iv) Multimerization and mechanisms for negative or positive
cooperativity of GPHR upon ligand binding and v) dimer- and oligomeric arrangements
enabling trans-activation on GPHR signaling are considered. Available knowledge concerning
the modulation of the GPHR (mal)-function and associated structural aspects by diverse
entities such as antibodies, chaperones, peptides, small molecule agonists, inverse
agonists, and antagonists is summarized. The TSHR is important with respect to autoimmune
[Graves’ disease (GD), Graves’ orbitopathy (GO)] or non-autoimmune thyroid dysfunctions
and cancer-development. To date there is neither an agonist nor antagonist modulator
of pathogenic such as TSHR signaling in the clinics. However, several different
ligands monoclonal stimulating and inhibiting antibodies and small molecule drug-like
ligands have been reported in the last decade. In special focus are the most recent
findings regarding the development and use of small molecule TSHR ligands. Finally,
limitations of current knowledge and lack of information are discussed highlighting
the need for intensified efforts towards understanding the interplay of TSHR multimers,
especially their interaction with drug-like ligands. Important in this context is
the biased ligand development.
Key words
TSH-receptor antibodies - Graves’ disease - thyroid-stimulating hormone - follicotropin
receptor - lutropin receptor - allosteric small drug-like molecules
