Progress in understanding structure‐function relationships of human thyroid‐stimulating hormone

Abstract

This paper summarizes current advances in the structure-function relationships of human thyroid-stimulating hormone (TSH) in the context of studies on structurally related gonadotropins. Investigators have now identified specific domains in both protein and carbohydrate components of human TSH that play distinct roles in the synthesis, bioactivity, and metabolic clearance of human TSH. The principles revealed in such studies are essential to understand mechanisms of receptor activation and permit design of novel analogues with potential clinical applications. In particular, superagonists of human TSH and human chorionic gonadotropin have been recently developed using a rational approach combining evolutionary considerations, sequence comparisons, and homology modeling. Such analogues with major increases in receptor-binding affinity and signal transduction are unique tools for studies of both thyroidal and extrathyroidal actions of TSH. Moreover, similar strategies may be used to design analogues of other members of the cystine knot growth factor superfamily.