Release date: 2018-03-09
The paper first reported the near-atomic resolution structure of the human splicing component SF3b complex combined with small molecule drugs, providing important structural information for understanding the mechanism of action of these drugs, and searching for splice-targeted drugs using cryo-electron microscopy. Provide ideas.
RNA splicing abnormalities are closely related to cancer. Somatic mutations in the splice protein component have been found in many common cancers such as myeloma, lymphoma, skin cancer, and breast cancer. Most of these cancer-related mutations are distributed on the SF3b1 component of the splice SF3b complex, so SF3b1 has always been one of the important targets for the treatment of cancer. The first splicing target drug to enter clinical trials was E7107. Biochemical experiments in vitro showed that E7107 can specifically bind to SF3b1 and inhibit the splicing reaction, but its mechanism of action is still unclear.
In this study, Finci et al. used a cryo-electron microscopy technique to obtain a high resolution structure of the SF3b complex in combination with the small molecule drug E7107 (Fig. 1A). This structure shows that E7107 interacts with a conserved sequence of SF3b1 (Fig. 1B). In this group of previous splice constructs, this sequence binds to a branch sequence of pre-mRNA. Such results suggest a competitive binding mechanism. In order to verify this mechanism of action, they mutated some of the amino acids in this sequence and found that the cells were resistant to E7107 after transformation; they also designed an in vitro competitive assay of E7107 and its derivatives with pre-mRNA. Finally, based on structural and biochemical data, they proposed a conjecture that E7107 competes with pre-mRNA for binding to SF3b1, thereby regulating the splicing reaction. In addition, this is the first structure of a splice-associated complex that combines small molecule inhibitors, which is important for understanding the mechanism of action of drugs and the regulation of RNA splicing.
Figure 1. SF3b complex binds to small molecule drug E7107
Lorenzo Finci is the first author and co-author of this article. Zhang Xiaofeng, Huang Xiuliang and Zhou Qiang from Tsinghua University made important contributions to the project. Nicholas Larsen from H3 Biomedicine is co-author of this article, Jennifer Tsai, Teng Teng, Anant Agrawal, Betty Chan, Sean Irwin, Craig Karr, Andrew Cook, Ping Zhu, Dominic Reynolds, Peter G Smith, Peter Fekkes, Silvia Buonamici Made an important contribution. This project has received strong support from Tsinghua University's cryo-electron microscopy platform, high-performance computing platform, and National Protein Facility Experimental Technology Center (Beijing). This work has been funded by the Beijing Center for Structural Biology and Advanced Innovation Center. Funded by the Natural Science Foundation and the Ministry of Science and Technology. Professor Shi Yigong guided the subject and provided many suggestions and help.
This article links:
Http://genesdev.cshlp.org/content/32/3-4/309.full
Source: Highly sophisticated innovation center for structural biology
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