Hormone Binding to the Follicle-Stimulating Hormone Receptor - Crystal Clear!

Abstract

The receptors for the trophic hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyrotropin (TSH) play a central role in endocrinology. These receptors face the challenge to accommodate large heterodimeric glycoprotein ligands within their extracellular hormone-binding domain. Until recently, the mechanism of hormone binding and consequently the mode of receptor activation remained enigmatic. By solving the crystal structure of human follicle-stimulating hormone bound to the receptor's hormone binding domain, it has become clear that the follicle-stimulating hormone receptor grabs the glycoprotein hormone in a hand-clasp mode resulting in a hormone orientation perpendicular to the long axis of the ligand-binding domain. These findings have important ramifications for our understanding of the molecular mechanism of receptor activation and may provide a rational basis for the development of small, non-peptidic FSH receptor ligands.

Evidence for cooperative signal triggering at the extracellular loops of the TSH receptor

“…Hormone binding and participating interactions at the LRRD of GPHRs have been experimentally investigated (4 -11). The crystal structure of the FSHR LRRD/FSH complex (12) has given detailed insights into the orientation of the hormone docked to the LRRD (13,14). Furthermore, contacts between the TSHR and activating or inactivating antibodies (15)(16)(17) have been substantiated by the crystal structure of the TSHR-LRRD in complex with an activating monoclonal autoantibody (18).…”