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The structure and function of the ghrelin receptor coding for drug actions
Yuki Shiimura1,2, Dohyun Im3, Ryosuke Tany4
1Division of Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka, Japan. shiimura_yuuki@kurume-u.ac.jp.
Nature Structural & Molecular Biology
|January 20, 2025
Summary
Anamorelin, a ghrelin receptor drug, shows superagonistic activity. Structural insights reveal how different drug structures impact receptor signaling and can personalize treatment based on genetic variations for anorexia, obesity, and diabetes.
Area of Science:
- Pharmacology and Structural Biology
- Endocrinology and Metabolic Diseases
Background:
- Ghrelin receptor (GHSR) targeted drugs show promise for anorexia, obesity, and diabetes.
- Developing effective GHSR modulators is hindered by complex drug-target interactions.
Purpose of the Study:
- To elucidate the structural basis of anamorelin's action at the ghrelin receptor.
- To compare anamorelin's mechanism with other synthetic ghrelin receptor ligands.
- To explore the role of structural information in understanding drug efficacy and genetic variations.
Main Methods:
- Co-crystallization of the ghrelin receptor with anamorelin and a miniGq protein.
- Structural analysis to determine ligand-receptor interactions and conformational changes.
- Assessment of signaling bias induced by different ligands and identification of genetic variants.
Main Results:
- Anamorelin exhibits superagonistic activity at the ghrelin receptor.
- Distinct ligand chemical structures induce unique receptor conformations and biased signaling.
- Structural insights facilitate the identification of genetic variations impacting drug response.
Conclusions:
- Structural elucidation of anamorelin-bound ghrelin receptor provides a framework for drug design.
- Understanding ligand-induced signaling bias and genetic variations enables personalized therapeutic strategies.
- This approach enhances the selection of effective ghrelin receptor-targeting medications.
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