The pseudokinase (PK) RNase L is a functional ribonuclease and plays important roles in human innate immunity. The ribonuclease activity of RNase L can be regulated by the kinase inhibitor sunitinib. The combined use of oncolytic virus and sunitinib has been shown to exert synergistic effects in anticancer therapy. In this study, we aimed to uncover the mechanism of action through which sunitinib inhibits RNase L. We solved the crystal structures of RNase L in complex with sunitinib and its analogs toceranib and SU11652. Our results showed that sunitinib bound to the ATP-binding pocket of RNase L. Unexpectedly, the αA helix linking the ankyrin repeat-domain and the PK domain affected the binding mode of sunitinib and resulted in an unusual flipped orientation relative to other structures in PDB. Molecular dynamics simulations and dynamic light scattering results support that the binding of sunitinib in the PK domain destabilized the dimer conformation of RNase L and allosterically inhibited its ribonuclease activity. Our study suggested that dimer destabilization could be an effective strategy for the discovery of RNase L inhibitors and that targeting the ATP-binding pocket in the PK domain of RNase L was an efficient approach for modulating its ribonuclease activity.
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September 2020
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Cover Image
Cover Image
The cover image is of a molecularly modelled receptor heterodimeric complex in its ligand bound active state (left), juxtaposed to uncomplexed receptors (right) in the presence of the proof of concept inhibitor which prevents ligand bound complex formation. For more information, see the article by Colomba and colleagues (pp. 3329–3347). The image was created by Phospho Biomedical Animation and provided by Peter Parker.
Research Article|
September 17 2020
Sunitinib inhibits RNase L by destabilizing its active dimer conformation
Jinle Tang
;
Jinle Tang
*
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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Yingjie Wang;
Huan Zhou;
Huan Zhou
*
3Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shang Hai, China
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Yuxin Ye;
Yuxin Ye
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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Manisha Talukdar;
Manisha Talukdar
4Department of Molecular Genetics and Department of Biochemistry, University of Toronto, Toronto, Canada
5Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
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Ziyang Fu;
Ziyang Fu
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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Zhihong Liu;
Zhihong Liu
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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Jihui Li;
Jihui Li
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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Dante Neculai;
Dante Neculai
6Department of Cell Biology, Zhejiang University, School of Basic Medical Sciences, Hangzhou, China
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Jiali Gao;
Jiali Gao
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
2Shenzhen Bay Laboratory, Shenzhen, China
7Department of Chemistry, University of Minnesota, Minneapolis, U.S.A.
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Hao Huang
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Correspondence: Hao Huang (huang.hao@pku.edu.cn)
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Biochem J (2020) 477 (17): 3387–3399.
Article history
Received:
March 28 2020
Revision Received:
July 27 2020
Accepted:
August 24 2020
Accepted Manuscript online:
August 24 2020
Citation
Jinle Tang, Yingjie Wang, Huan Zhou, Yuxin Ye, Manisha Talukdar, Ziyang Fu, Zhihong Liu, Jihui Li, Dante Neculai, Jiali Gao, Hao Huang; Sunitinib inhibits RNase L by destabilizing its active dimer conformation. Biochem J 18 September 2020; 477 (17): 3387–3399. doi: https://doi.org/10.1042/BCJ20200260
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