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The molecular basis for growth hormone-receptor interactions
J A Wells1, B C Cunningham, G Fuh
1Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080.
Recent Progress in Hormone Research
|January 1, 1993
Summary
Human growth hormone (hGH) action involves binding to its receptor via two sites, leading to dimerization and signaling. Engineered antagonists block this process, offering insights into hormone receptor interactions.
Area of Science:
- Molecular endocrinology
- Hormone receptor signaling
- Protein engineering
Background:
- High-resolution analyses reveal the molecular basis of human growth hormone (hGH) action.
- Structural and functional studies have elucidated hGH-receptor interactions.
- Engineered hGH analogs can act as antagonists or selective agonists.
Purpose of the Study:
- To elucidate the molecular mechanism of hGH receptor activation.
- To engineer hGH analogs with altered receptor binding properties.
- To develop antagonists for hGH and related hormone receptors.
Main Methods:
- Alanine scanning mutagenesis
- Monovalent phage display
- Structural and mutational analyses of hGH and its receptor
- Engineering of hGH receptor antagonists
Main Results:
- hGH binds the hGH receptor via site 1, then dimerizes through site 2.
- A similar mechanism, requiring Zn2+, is proposed for hGH activation of the hPRL receptor.
- Potent antagonists were developed that bind site 1 but block receptor dimerization.
- Engineered analogs demonstrated receptor selectivity and high affinity.
Conclusions:
- The mechanism of hGH receptor activation involves sequential binding and dimerization.
- Engineered antagonists provide tools to study and potentially modulate hGH signaling.
- These findings have implications for understanding other hormone-receptor systems.