Crystal Structure Analysis of Ghrelin Receptor

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K16217
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kurume University
• Principal Investigator: Shiimura Yuki 久留米大学, 付置研究所, 助教 (40551297)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: グレリン受容体 / GPCR / 構造生物学

Outline of Final Research Achievements

The ghrelin receptor (previously called GHSR) plays a central role in regulating appetite, making it an attractive target for treatment of obesity. The endogenous agonist ghrelin, found in the stomach promotes appetite and is responsible for opposing the signaling of leptin in the body. To clarify how octanoic acid-modified ghrelin is recognized by the ghrelin receptor, the structure of the ghrelin receptor in a ghrelin-bound state was determined. The structural information showed that the binding pocket of the ghrelin receptor is divided into two parts, a large and a small pocket. The large pocket contained the peptide portion of ghrelin, while the small pocket contained the octanoic acid portion. In other words, the ghrelin receptor recognizes octanoic acid-modified ghrelin by skillfully utilizing the characteristics of this ligand-binding pocket.

Free Research Field

内分泌学

Academic Significance and Societal Importance of the Research Achievements

グレリン受容体アゴニスト (アナモレリン) は、食欲の低下とそれに伴う体重や筋肉量の減少を示す、がん悪液質の治療薬として唯一認められている医薬品である。がんカヘキシアはがん患者の死因の1/4を占めているため、より効果のある医薬品開発が期待されている。グレリン受容体アゴニストはそれ以外にも拒食症や食欲不振といった病態に応用できる可能性があり創薬ターゲットとしての期待度が高い。本研究では、グレリンと結合状態にあるグレリン受容体の構造を決定し、それらの結合様式を明らかにした。これらの結果は、グレリン受容体を対象にした構造情報に基づいた医薬品開発を加速させると考える。