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Structural and Functional Characterization of Rv0792c from Mycobacterium tuberculosis: Identifying Small Molecule Inhibitor against HutC Protein

Chauhan, NK and Anand, A and Sharma, A and Dhiman, K and Gosain, TP and Singh, P and Singh, P and Khan, E and Chattopadhyay, G and Kumar, A and Sharma, D and Ashish, A and Sharma, TK and Singh, R (2023) Structural and Functional Characterization of Rv0792c from Mycobacterium tuberculosis: Identifying Small Molecule Inhibitor against HutC Protein. In: Microbiology Spectrum, 11 (1).

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Official URL: https://10.1128/spectrum.01973-22


In order to adapt in host tissues, microbial pathogens regulate their gene expression through a variety of transcription factors. Here, we have functionally characterized Rv0792c, a HutC homolog from Mycobacterium tuberculosis. In comparison to the parental strain, a strain of M. tuberculosis with a Rv0792c mutant was compromised for survival upon exposure to oxidative stress and infection in guinea pigs. RNA sequencing analysis revealed that Rv0792c regulates the expression of genes involved in stress adaptation and virulence of M. tuberculosis. Solution small-angle X-ray scattering (SAXS) data-steered model building confirmed that the C-terminal region plays a pivotal role in dimer formation. Systematic evolution of ligands by exponential enrichment (SELEX) resulted in the identification of single-strand DNA (ssDNA) aptamers that can be used as a tool to identify small-molecule inhibitors targeting Rv0792c. Using SELEX and SAXS data-based modeling, we identified residues essential for Rv0792c’s aptamer binding activity. In this study, we also identified I-OMe-Tyrphostin as an inhibitor of Rv0792c’s aptamer and DNA binding activity. The identified small molecule reduced the growth of intracellular M. tuberculosis in macrophages. The present study thus provides a detailed shape-function characterization of a HutC family of transcription factor from M. tuberculosis. Copyright © 2022 Chauhan et al.

Item Type: Journal Article
Publication: Microbiology Spectrum
Publisher: American Society for Microbiology
Additional Information: The copyright of this article belongs to the Authors.
Keywords: Animals; Aptamers, Nucleotide; DNA; Guinea Pigs; Mycobacterium tuberculosis; Scattering, Small Angle; Transcription Factors; Tuberculosis; Tyrphostins; X-Ray Diffraction; aptamer; DNA; transcription factor; tyrphostin; animal; chemistry; genetics; guinea pig; metabolism; Mycobacterium tuberculosis; small angle scattering; tuberculosis; X ray diffraction
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 10 Mar 2023 10:13
Last Modified: 10 Mar 2023 10:13
URI: https://eprints.iisc.ac.in/id/eprint/80913

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