Elucidation of a complete picture of the activation mechanism of Toll-like receptors in lipid bilayers by multilevel analysis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03164
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Ohto Umeharu 東京大学, 大学院薬学系研究科(薬学部), 准教授 (90451856)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 自然免疫 / TLR受容体 / クライオ電子顕微鏡 / タンパク質 / 構造解析

Outline of Final Research Achievements

Structural biology of the full-length of innate immune receptor TLR was investigated. Cryo-EM structural analysis of full-length TLR3 reconstituted into nanodisc was successfully performed. The density of extracellular domain of TLR3 was clearly observed, but transmembrane regions and intracellular TIR domains were poorly resolved. The structures of TLR3-UNC93B1 and TLR7-UNC93B1 were successfully determined, revealing the structural basis of the regulation mechanism of nucleic acid-sensing TLR localization by UNC93B1.

Free Research Field

構造生命科学

Academic Significance and Societal Importance of the Research Achievements

種々の病気の治療薬開発のターゲットであるTLR受容体に関して構造生物学的な研究を進めた。TLR全長の活性化機構の全貌はいまだ明らかになっておらず、本研究は今後の研究の基盤となることが期待される。一部のTLRの細胞内局在を制御するUNC93B1とTLRの複合体の構造解析に成功し、TLRの細胞内局在を制御する薬剤開発の構造基盤を明らかにした。