Structure-based analysis of the central itch receptors aiming at development of new medicine for chronic itch and cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K07358
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Kansai Medical University
• Principal Investigator: INOUE Akitoshi 関西医科大学, 医学部, 助教 (50709152)
• Co-Investigator(Kenkyū-buntansha): 寿野 良二 関西医科大学, 医学部, 准教授 (60447521)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 痒み / Cryo EM SPA / 構造解析 / GRPR / NMBR / GPCR

Outline of Final Research Achievements

GRPR and NMBR, members of the G protein-coupled receptor (GPCR) family, serve as central itch receptors, transmitting itch-selective signals in the spinal cord. Therefore, GRPR and NMBR are important targets in the development of drugs for chronic pruritus such as atopic dermatitis, and structural information for drug discovery is needed. In this study, we employed a novel approach to generate various thermostabilized mutants that enable monodisperse purification of GRPR and NMBR. By conducting Cryo-Electron Microscopy Single-Particle Analysis (Cryo-EM SPA), we elucidated high-resolution three-dimensional structural information, including details of inhibitor binding.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では痒み伝達における中枢受容体であるGRPRとNMBRの様々な阻害剤結合情報を含む三次元立体構造情報を明らかにした。これらの情報を元にリガンドの選択性、非選択性に関わるアミノ酸配列を明らかにすることができる。これによりGRPRやNMBRをターゲットにしたリガンド開発を構造情報を元に効率よく行うことが可能となる。