2023 Fiscal Year Final Research Report
Elucidation of the dynamic structural basis controlling signal selectivity of the G protein-coupled receptor b2AR
| Project/Area Number |
21H02619
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
Imai Shunsuke 国立研究開発法人理化学研究所, 生命機能科学研究センター, 上級研究員 (20894413)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | GPCR / 溶液NMR / シグナル選択性 |
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| Outline of Final Research Achievements |
In this study, we aimed to unravel the structural basis governing signal selectivity in GPCRs, focusing on b2AR. We compared the dynamic structures of b2AR in the balanced ligand-bound state and the biased ligand-bound state to shed light on the underlying mechanisms.
Our approach involved subjecting the balanced ligand isoproterenol and the biased ligand isoetharine to NMR analysis. The results revealed that the ethyl group of isoetharine engages in a steric clash with residue F193 on the extracellular loop of b2AR. This collision alters the structue near A134 on the intracellular side of TM3 and A226 on the intracellular side of TM5.
Based on these findings, we propose that the intracellular structural changes observed in the presence of the biased ligand play a role in determining signal selectivity. This discovery provides new insights into the complex interplay between ligand binding and the resulting conformational changes that shape the signaling outcomes of GPCRs.
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| Free Research Field |
構造生物学
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| Academic Significance and Societal Importance of the Research Achievements |
GPCRのシグナル選択性は、薬の主作用と副作用のバランスを規定する可能性があるため、その機構の理解と制御は副作用を抑えたGPCR薬の開発において重要な課題である。本研究では、isoproterenolにエチル基が付加したisoetahrineが、なぜisoproterenolにはないシグナル選択性を示すのかを解析し、その違いがTM3やTM5の細胞内側の残基周辺の構造変化を誘起することを示した。この成果は、この領域の構造変化に着目することで既知化合物より強いシグナル選択性を示す新規バイアスリガンドを開発できる可能性を示した点において学術的および社会的意義を有する。
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