BINDING IN THE GROWTH-HORMONE RECEPTOR COMPLEX

Binding reactions between human growth hormone (hGH) and its receptor provide a detailed account of how a polypeptide hormone activates its receptor and more generally how proteins interact. Through high-resolu tion structural and functional studies it is seen that hGH uses two di fferent sites (site 1 and site 2) to bind two identical receptor molec ules, This sequential dimerization reaction activates the receptor, pr esumably by bringing the intracellular domains into close proximity so they may activate cytosolic components. As a consequence of this mech anism it is possible to build antagonists to the receptor by introduci ng mutations in hGH that block binding at site 2 and to build even mor e potent antagonists by combining these with mutants that enhance bind ing at site 1. Alanine-scanning mutagenesis of all contact residues at the site 1 interface shows that only a small and complementary set of side chains clustered near the center of the interface affects bindin g. The most important contacts are hydrophobic, and these are surround ed by polar and charged interactions of lesser importance. Kinetic ana lysis shows for the most part that the important side chains function to maintain the complex, not to guide the hormone to the receptor, Hor mone-induced homodimerization or heterodimerization reactions are turn ing out to be pervasive mechanisms for signal transduction. Moreover, the molecular recognition principles seen in the hGH-receptor complex are likely to generalize to other protein-protein complexes.