Biyani Madhu, Isogai Yasuhiro, Sharma Kirti, Maeda Shoei, Akashi Hinako, Sugai Yui, Nakano Masataka, Kodera Noriyuki, Biyani Manish, Nakajima Miki
Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan.
Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, Toyama, Japan.
Nat Commun. 2025 May 26;16(1):4757. doi: 10.1038/s41467-025-59987-6.
Targeting abnormal dysregulation of adenosine-to-inosine deamination by ADAR enzymes offers a promising therapeutic strategy in cancer research. However, the development of effective inhibitors is impeded by the incomplete structural information on ADAR1 complexes. In this study, we employ a combination of computational 3D modeling and high-speed atomic force microscopy to elucidate the atomic and molecular dynamics of ADAR1. Two distinct interface regions (IFx and IFy) on the surface of the deaminase domain and oligomerization structural models are identified. Single-molecule-level insights into the structural dynamics of ADAR1 reveal the oligomerization of ADAR1 monomers through the self-assembly of deaminase domains. In the presence of the substrate dsRNA, the N-terminal region, including RNA-binding domains, of ADAR1 dimer exhibits a controlled flexible conformation and promotes a stable dimeric interaction with dsRNA for RNA editing. These findings provide the basis for the development of targeted inhibitors to regulate ADAR1 activity in therapeutic applications.
通过ADAR酶靶向腺苷到肌苷脱氨基的异常失调，在癌症研究中提供了一种有前景的治疗策略。然而，ADAR1复合物不完整的结构信息阻碍了有效抑制剂的开发。在本研究中，我们采用计算三维建模和高速原子力显微镜相结合的方法来阐明ADAR1的原子和分子动力学。在脱氨酶结构域和寡聚化结构模型的表面鉴定出两个不同的界面区域（IFx和IFy）。对ADAR1结构动力学的单分子水平洞察揭示了ADAR1单体通过脱氨酶结构域的自组装进行寡聚化。在底物双链RNA存在的情况下，ADAR1二聚体的包括RNA结合结构域的N末端区域呈现可控的柔性构象，并促进与双链RNA的稳定二聚体相互作用以进行RNA编辑。这些发现为开发靶向抑制剂以在治疗应用中调节ADAR1活性提供了基础。
