Structural mechanism for PPARalpha regulation by endogenous amino acids

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16359
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: Kamata Shotaro 昭和薬科大学, 薬学部, 助教 (10823932)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: X線結晶構造解析 / PPAR

Outline of Final Research Achievements

The nuclear receptor PPARa regulates lipid metabolism and induces genes involved in fatty acid beta-oxidation and lipid transport. In this study, we aimed to clarify how endogenous amino acids inhibit PPARa by X-ray crystallography. We examined various conditions, such as delipidating of PPARa and adding a corepressor peptide could not confirm the binding of the target molecule even if crystals were formed. This study established the method for crystallization of various strong and weak PPARa ligands. These techniques have made it possible to obtain PPARa ligand complex structures with high resolution easily. In addition, the PPARa activity and binding sites are different between pemafibrate and other fibrates. PPARs are currently attracting attention as a therapeutic target for NASH, and we obtained both complex structures with saroglitazar, a PPARa/g dual agonist. These results will contribute to developing new PPAR therapeutics for NASH and other diseases.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

本研究によりPPARaの強弱様々なリガンドの結晶化法を確立した。これにより取得の難しかったPPARaリガンド複合体構造を高分解能で容易に得られるようになった。また、フィブラート系薬でも近年認可されたPemafibrateとそれ以外ではPPARa活性と結合部位ともに異なっており、今回得られた構造と治療効果や副作用に関連があるか今後確認する必要がある。現在、PPARはNASHの治療ターゲットとして注目されており、PPARa/g デュアルアゴニストのSaroglitazarについては両方の複合体構造を取得した。これらの結果はNASHを始めとする新たなPPAR治療薬の創出に貢献する。