Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

TLDR

Receptor dimerization occurs sequentially, with a first receptor binding to site 1 on hGH followed by a second receptor binding to site 2. The study aimed to design inactive hGH analogs that act as potent antagonists of hGH‑induced cell proliferation based on this sequential dimerization mechanism. A hybrid receptor fusing the hGH extracellular domain to murine G‑CSF transmembrane and intracellular domains was built, and inactive hGH analogs were engineered to block the dimerization‑dependent signaling that requires two receptor molecules. hGH stimulation of the hybrid‑receptor‑expressing FDC‑P1 cells induced proliferation, while the engineered antagonists could inhibit this effect and may be useful for treating hGH‑excess disorders such as acromegaly.

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.