Crystal Structure of an Antagonist Mutant of Human Growth Hormone, G120R, in Complex with Its Receptor at 2.9 Å Resolution

• Published in: The Journal of biological chemistry 1996-12, Vol.271 (50), p.32197-32203
• Main Authors: Sundström, Michael, Lundqvist, Tomas, Rödin, Joakim, Giebel, Lutz B., Milligan, Dan, Norstedt, Gunnar
• Format: Article
• Language: English
• Subjects: Crystallography, X-Ray; Growth Hormone - analogs & derivatives; Growth Hormone - chemistry; Growth Hormone - metabolism; Hormone Antagonists - chemistry; Hormone Antagonists - metabolism; Human Growth Hormone - chemistry; Human Growth Hormone - metabolism; Humans; Hydrogen Bonding; Medicin och hälsovetenskap; Models, Molecular; Molecular Sequence Data; Receptors, Somatotropin - metabolism; Recombinant Proteins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.271.50.32197

Human growth hormone binds two receptor molecules and thereby induces signal transduction through receptor dimerization. At high concentrations, growth hormone acts as an antagonist because of a large difference in affinities at the respective binding sites. This antagonist action can be enhanced further by reducing binding in the low affinity binding site. A growth hormone antagonist mutant Gly-120 → Arg, has been crystallized with its receptor as a 1:1 complex and the crystal structure determined at 2.9 Å resolution. The 1:1 complex is remarkably similar to the native growth hormone-receptor 1:2 complex. A comparison between the two structures reveals only minimal differences in the 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 hormone-human growth hormone-binding protein 1:2 complex structure at 2.5 Å resolution. One important difference between our structure and the previously published crystal structure at 2.8 Å is revealed. Trp-104 in the receptor, a key residue in the hormone-receptor interaction, has an altered conformation in the low affinity site enabling a favorable hydrogen bond to be formed with Asp-116 of the hormone.