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结合蛋白（RbpA）对结核分枝杆菌RNA聚合酶组装动力学影响的计算分析

Computational analysis of the effect of a binding protein (RbpA) on the dynamics of Mycobacterium tuberculosis RNA polymerase assembly.

作者信息

Bheemireddy Sneha, Sowdhamini Ramanathan, Srinivasan Narayanaswamy

机构信息

Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, Karnataka, India.

National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bengaluru, Karnataka, India.

出版信息

PLoS One. 2025 Jan 30;20(1):e0317187. doi: 10.1371/journal.pone.0317187. eCollection 2025.

DOI:10.1371/journal.pone.0317187
PMID:39883746
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11781615/
Abstract

BACKGROUND

RNA polymerase-binding protein A (RbpA) is an actinomycetes-specific protein crucial for the growth and survival of the pathogen Mycobacterium tuberculosis. Its role is essential and influences the transcription and antibiotic responses. However, the regulatory mechanisms underlying RbpA-mediated transcription remain unknown. In this study, we employed various computational techniques to investigate the role of RbpA in the formation and dynamics of the RNA polymerase complex.

RESULTS

Our analysis reveals significant structural rearrangements in RNA polymerase happen upon interaction with RbpA. Hotspot residues, crucial amino acids in the RbpA-mediated transcriptional regulation, were identified through our examination. The study elucidates the dynamic behavior within the complex, providing insights into the flexibility and functional dynamics of the RbpA-RNA polymerase interaction. Notably, potential allosteric mechanisms, involving the interface of subunits α1 and α2 were uncovered, shedding light on how RbpA modulates transcriptional activity.

CONCLUSIONS

Finally, potential ligands meant for the α1-α2 binding site were identified through virtual screening. The outcomes of our computational study serve as a foundation for experimental investigations into inhibitors targeting the RbpA-regulated dynamics in RNA polymerase. Overall, this research contributes valuable information for understanding the intricate regulatory networks of RbpA in the context of transcription and suggests potential avenues for the development of RbpA-targeted therapeutics.

摘要

背景

RNA聚合酶结合蛋白A（RbpA）是一种放线菌特异性蛋白，对结核分枝杆菌病原体的生长和存活至关重要。其作用至关重要，影响转录和抗生素反应。然而，RbpA介导的转录的调控机制仍不清楚。在本研究中，我们采用了各种计算技术来研究RbpA在RNA聚合酶复合物形成和动力学中的作用。

结果

我们的分析表明，RNA聚合酶与RbpA相互作用时会发生显著的结构重排。通过我们的研究确定了热点残基，即RbpA介导的转录调控中的关键氨基酸。该研究阐明了复合物中的动态行为，为RbpA-RNA聚合酶相互作用的灵活性和功能动力学提供了见解。值得注意的是，发现了涉及α1和α2亚基界面的潜在变构机制，揭示了RbpA如何调节转录活性。

结论

最后，通过虚拟筛选确定了针对α1-α2结合位点的潜在配体。我们的计算研究结果为针对RNA聚合酶中RbpA调节动力学的抑制剂的实验研究奠定了基础。总体而言，这项研究为理解转录背景下RbpA的复杂调控网络提供了有价值的信息，并为开发针对RbpA的治疗方法提出了潜在途径。

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