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

Abstract

がん悪液質治療薬アナモレリンが結合したグレリン受容体構造を解明 創薬、個別化医療への道を拓く構造・薬理学情報を拡充. 京都大学プレリリース. 2025-01-21Drugs 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 miniGq, 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