Allosteric Modulators Hit the TSH Receptor

Abstract

The receptor for TSH (TSHR) has captured our interest and imagination since it was first demonstrated to be a major human antigen in autoimmune thyroid disease. The original realization that the immunoglobulin fraction of sera from patients with Graves' disease incorporated unique human autoantibodies to the TSHR led to the unraveling of the great complexity that the TSHR exhibits in comparison with its orthologous partners; the LH and FSH receptors (1, 2). The TSHR is a member of the class A G-protein coupled receptor (GPCR) family with 7 transmembrane regions. The holoreceptor consists of 764 amino acids divided into a large, highly glycosylated, ectodomain of 415 amino acids incorporating 11 leucine rich repeats and which has been crystallized bound to a stimulating TSHR antibody (3). The ectodomain is linked to a distal signal-specific domain, which is a hinge region of 130 amino acids. The hinge region is attached to a transmembrane domain (TMD) of 349 amino acids typical of the GPCR family incorporating 7 transmembrane helices (TMHs) joined by extracellular (ECL) and intracellular (ICL) loops (Figure 1).