Reports

Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

Science  19 Jun 1992:
Vol. 256, Issue 5064, pp. 1677-1680
DOI: 10.1126/science.256.5064.1677

Abstract

A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially—a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH- induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

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