The structure and function of the ghrelin receptor coding for drug actions

Yuki Shiimura; Dohyun Im; Ryosuke Tany; Hidetsugu Asada; Ryoji Kise; Eon Kurumiya; Hideko Wakasugi-Masuho; Satoshi Yasuda; Kazuma Matsui; Jun-Ichi Kishikawa; Takayuki Kato; Takeshi Murata; Masayasu Kojima; So Iwata; Ikuo Masuho

doi:10.1038/s41594-024-01481-6

The structure and function of the ghrelin receptor coding for drug actions

Nat Struct Mol Biol. 2025 Jan 20. doi: 10.1038/s41594-024-01481-6. Online ahead of print.

Authors

Yuki Shiimura^#^{1

2}, Dohyun Im^#³, Ryosuke Tany^#⁴, Hidetsugu Asada³, Ryoji Kise⁴, Eon Kurumiya⁴, Hideko Wakasugi-Masuho⁴, Satoshi Yasuda^{5

6}, Kazuma Matsui⁷, Jun-Ichi Kishikawa^{8

9}, Takayuki Kato⁸, Takeshi Murata^{5

6}, Masayasu Kojima⁷, So Iwata¹⁰, Ikuo Masuho^{11

12}

Affiliations

¹ Division of Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka, Japan. [email protected].
² Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [email protected].
³ Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁴ Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA.
⁵ Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan.
⁶ Membrane Protein Research Center, Chiba University, Chiba, Japan.
⁷ Division of Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka, Japan.
⁸ Institute for Protein Research, Osaka University, Osaka, Japan.
⁹ Faculty of Applied Biology, Kyoto Institute of Technology, Kyoto, Japan.
¹⁰ Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [email protected].
¹¹ Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA. [email protected].
¹² Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA. [email protected].

^# Contributed equally.

PMID: 39833471
DOI: 10.1038/s41594-024-01481-6

Abstract

Drugs targeting the ghrelin receptor hold therapeutic potential in anorexia, obesity and diabetes. However, developing effective drugs is challenging. To tackle this common issue across a broad drug target, this study aims to understand how anamorelin, the only approved drug targeting the ghrelin receptor, operates compared to other synthetic drugs. Our research elucidated the receptor's structure with anamorelin and miniG_q, unveiling anamorelin's superagonistic activity. We demonstrated that ligands with distinct chemical structures uniquely bind to the receptor, resulting in diverse conformations and biasing signal transduction. Moreover, our study showcased the utility of structural information in effectively identifying natural genetic variations altering drug action and causing severe functional deficiencies, offering a basis for selecting the right medication on the basis of the individual's genomic sequence. Thus, by building on structural analysis, this study enhances the foundational framework for selecting therapeutic agents targeting the ghrelin receptor, by effectively leveraging signaling bias and genetic variations.