Binding of small molecule inhibitors to RNA polymerase-Spt5 complex impacts RNA and DNA stability

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Adan Gallardo, Bercem Dutagaci
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引用次数: 0

Abstract

Spt5 is an elongation factor that associates with RNA polymerase II (Pol II) during transcription and has important functions in promoter-proximal pausing and elongation processivity. Spt5 was also recognized for its roles in the transcription of expanded-repeat genes that are related to neurodegenerative diseases. Recently, a set of Spt5-Pol II small molecule inhibitors (SPIs) were reported, which selectively inhibit mutant huntingtin gene transcription. Inhibition mechanisms as well as interaction sites of these SPIs with Pol II and Spt5 are not entirely known. In this study, we predicted the binding sites of three selected SPIs at the Pol II-Spt5 interface by docking and molecular dynamics simulations. Two molecules out of three demonstrated strong binding with Spt5 and Pol II, while the other molecule was more loosely bound and sampled multiple binding sites. Strongly bound SPIs indirectly affected RNA and DNA dynamics at the exit site as DNA became more flexible while RNA was stabilized by increased interactions with Spt5. Our results suggest that the transcription inhibition mechanism induced by SPIs can be related to Spt5-nucleic acid interactions, which were altered to some extent with strong binding of SPIs.

Abstract Image

小分子抑制剂与RNA聚合酶- spt5复合物的结合影响RNA和DNA的稳定性。
Spt5是一种延伸因子,在转录过程中与RNA聚合酶II (Pol II)结合,在启动子-近端暂停和延伸过程中具有重要作用。Spt5也被认为在与神经退行性疾病相关的扩展重复基因的转录中发挥作用。最近,一组Spt5-Pol II小分子抑制剂(SPIs)被报道,选择性抑制突变型亨廷顿蛋白基因的转录。这些spi的抑制机制以及与Pol II和Spt5的相互作用位点尚不完全清楚。在这项研究中,我们通过对接和分子动力学模拟预测了三种SPIs在Pol II-Spt5界面上的结合位点。三个分子中有两个分子与Spt5和Pol II结合较强,而另一个分子结合较松散,具有多个结合位点。强结合的sp5间接影响了退出位点的RNA和DNA动力学,因为DNA变得更灵活,而RNA通过增加与Spt5的相互作用而稳定。我们的研究结果表明SPIs诱导的转录抑制机制可能与spt5 -核酸相互作用有关,SPIs的强结合在一定程度上改变了spt5 -核酸相互作用。
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来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
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