Sunitinib inhibits RNase L by destabilizing its active dimer conformation
Sunitinib inhibits RNase L by destabilizing its active dimer conformation
复制标题
舒尼替尼通过破坏其活性二聚体构象来抑制 RNase L
DOI：
10.1042/bcj20200260
复制
发表时间：
2020
影响因子：
4.1
通讯作者：
Hao Huang
中科院分区：
文献类型：
--
作者：
Jinle Tang;Yingjie Wang;Huan Zhou;Yuxin Ye;Manisha Talukdar;Ziyang Fu;Zhihong Liu;Jihui Li;Dante Neculai;Jiali Gao;Hao Huang
伪激酶(PK)核糖核酸酶L是一种功能性核糖核酸酶，在人类先天免疫中发挥重要作用。核糖核酸酶L的核糖核酸酶活性可被激酶抑制剂孙尼替尼调节。溶瘤病毒和舒尼替尼的联合应用已被证明在抗癌治疗中具有协同作用。本研究旨在揭示舒尼替尼抑制核糖核酸酶L的作用机制。我们解开了舒尼替尼及其类似物与舒尼替尼和SU11652形成的核糖核酸酶L的晶体结构。我们的结果表明，苏尼替尼与RNaseL的三磷酸腺苷结合口袋结合。意外的是，连接Ankyrin重复结构域和PK结构域的αA螺旋影响了Sunitinib的结合模式，并导致了相对于PDB中其他结构的不寻常的反转取向。分子动力学模拟和动态光散射结果表明，舒尼替尼与核糖核酸酶PK结构域的结合破坏了核糖核酸酶L的二聚体构象，并变构抑制了核糖核酸酶的活性。我们的研究表明，二聚体失稳可能是发现核糖核酸酶L抑制剂的有效策略，靶向核糖核酸酶L PK结构域的ATP结合口袋是调节其核糖核酸酶活性的有效途径。
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.