CRYSTAL-STRUCTURE OF AN ANTAGONIST MUTANT OF HUMAN GROWTH-HORMONE, G120R, IN COMPLEX WITH ITS RECEPTOR AT 2.9 ANGSTROM RESOLUTION

Human growth hormone binds two receptor molecules and thereby induces signal transduction through receptor dimerization. At high concentrati ons, growth hormone acts as an antagonist because of a large differenc e in affinities at the respective binding sites, This antagonist actio n can be enhanced further by reducing binding in the low affinity bind ing site, A growth hormone antagonist mutant Gly-120 --> Arg, has been crystallized with its receptor as a 1:1 complex and the crystal struc ture determined at 2.9 Angstrom resolution. The 1:1 complex is remarka bly similar to the native growth hormone-receptor 1:2 complex, A compa rison between the two structures reveals only minimal differences in t he conformations of the hormone or its receptor in the two complexes, including the angle between the two immunoglobulin-like domains of the receptor, Further, two symmetry-related 1:1 complexes in the crystal form a 2:2 complex with a large solvent inaccessible area between two receptor molecules, In addition, we present here a native human growth hormon-human growth hormone-binding protein 1:2 complex structure at 2.5 Angstrom resolution, One important difference between our structur e and the previously published crystal structure at 2.8 Angstrom is re vealed. Trp-104 in the receptor, a key residue in the hormone-receptor interaction, has an altered conformation in the low affinity site ena bling a favorable hydrogen bond to be formed with Asp-116 of the hormo ne.