2023 Fiscal Year Final Research Report

Development of a platform for rapid structural analysis of transient protein complexes.

Planned Research

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Project Area	Multi-scale platform for untangling physiological complexity
Project/Area Number	21H05112
Research Category	Grant-in-Aid for Transformative Research Areas (B)
Allocation Type	Single-year Grants
Review Section	Transformative Research Areas, Section (II)
Research Institution	Kansai Medical University
Principal Investigator	SUNO Ryoji 関西医科大学, 医学部, 准教授 (60447521)
Co-Investigator(Kenkyū-buntansha)	加藤貴之大阪大学, 蛋白質研究所, 教授 (20423155) 藤田大士京都大学, 高等研究院, 准教授 (20713564)
Project Period (FY)	2021-08-23 – 2024-03-31
Keywords	GPCR / クライオ電子顕微鏡単粒子解析 / シグナル伝達 / SBDD / 膜タンパク質 / 鎮痛
Outline of Final Research Achievements	In this research area, complex physiological actions that emerge as multidimensional outputs are examined by breaking them down into the dimensions of molecules (Suno Group), cells (Inoue Group), individuals (Sakurai Group) and regulation (Saito Group), and are described and visualised in the form of superposition of "elementary processes" at the scale of molecules, cells and individuals. The Suno group is in charge of the molecular phase and aims to clarify the whole picture of the signalling mechanism via opioid receptors (κ and δ opioid receptors (KOR and DOR)) at the atomic resolution level by single particle analysis using cryo-electron microscopy. The structures of three biased ligand-bound states in the KOR and one balanced ligand-bound state in the DOR and one balanced ligand-bound state in the KOR and DOR, respectively, have been determined.
Free Research Field	構造生物学、医化学
Academic Significance and Societal Importance of the Research Achievements	μ、δ、κオピオイド受容体（MOR, DOR, KOR)の作動薬は鎮痛効果があり、とくにMORの作動薬であるモルヒネはがん性疼痛などに顕著な効果を示す。一方で、薬物依存などの重篤な副作用を示すため、その使用法は制限されている。多くの製薬企業などの研究機関がMOR作動薬の副作用を軽減する努力が長年行われてきたが未だに成功していない。本研究では鎮痛効果を示すDOR, KORの作動薬に着目し、様々な性質をもつ作動薬が結合したDOR, KORの立体構造を決定した。副作用を示す作動薬と副作用が弱い作動薬の結合状態を比較し、副作用の発現メカニズムを検討した。この構造情報は副作用のない薬剤開発に貢献できる。