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Volume 271, Number 50, Issue of December 13, 1996 pp. 32197-32203
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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

(Received for publication, March 27, 1996, and in revised form, July 3, 1996)

Michael Sundström , Tomas Lundqvist , Joakim Rödin " , Lutz B. Giebel ''' , Dan Milligan ''' and Gunnar Norstedt dagger

From the Departments of  Structural Biochemistry, " Biochemistry, and dagger  Cell Biology, Pharmacia and Upjohn, Preclinical Research and Development, S-112 87 Stockholm, Sweden, and the ''' Arris Pharmaceutical Corporation, South San Francisco, California 94080

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 right-arrow 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.


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