Graduate Student Aarshi Singh

"Structural insights into the Mycobacterium tuberculosis White B-like (Wbl) Family of Transcription Factor "

Mycobacterium tuberculosis (Mtb) is the pathogen that causes pulmonary tuberculosis (TB). The treatment for TB is complicated because it involves several drugs that need to be administered for several months. Often patients do not finish the course due to which several strains of Mtb have developed resistance to the first- and second-line drugs. In addition, treatment for TB can be delayed due to the Mtb’s ability to enter dormancy where it is non-replicating and has a decreased virulence. Upon immune system suppression, the infection can become active again. Bacterial transcription has been best characterized in E. coli which belongs to the γ-proteobacteria phyla, whereas Mtb belongs to the actinobacteria phyla. Therefore, the details about transcription and how Mtb genetically evolved to overcome the stresses faced during infection remain unclear. White-B-like (Wbl) proteins are actinobacteria-specific transcription factors that are prevalent in this family and are essential for bacterial growth1. Wbl proteins are subdivided into five classes, each of which plays a significant role in bacterial virulence and antibiotic resistance. Despite their known importance, Wbl proteins remain enigmatic due to a lack of their structural information.

In my talk I will discuss structural insights into Mtb Wbl class I WhiB1 protein and class V WhiB7 protein. Firstly, the structure of WhiB1 will be discuss in detail which contains the [4Fe-4S] cluster held together with three ⍺-helices and a glycine rich motif2. I will also discuss WhiB1’s cluster disassembly upon reacting with nitric oxide (NO). Secondly, WhiB1 binding to σA in a non-canonical manner and structural changes to allow for DNA binding will be discussed3. Lastly, I will discuss the structure of WhiB7, a protein that induces antibiotic resistance in Mtb, in complex with σA binding to its promoter4. Structural information about WhiB proteins can provide mechanistic insights into Mtb’s intrinsic antibiotic resistance and entry into dormancy.

References
(1) Bush, M. J. The Actinobacterial WhiB-like (Wbl) Family of Transcription Factors: The Actinobacterial WhiB-like (Wbl) Family of Transcription Factors. Mol. Microbiol. 2018, 110 (5), 663–676. https://doi.org/10.1111/mmi.14117.
(2) Kudhair, B. K.; Hounslow, A. M.; Rolfe, M. D.; Crack, J. C.; Hunt, D. M.; Buxton, R. S.; Smith, L. J.; Le Brun, N. E.; Williamson, M. P.; Green, J. Structure of a Wbl Protein and Implications for NO Sensing by M. Tuberculosis. Nat. Commun. 2017, 8 (1), 2280. https://doi.org/10.1038/s41467-017-02418-y.
(3) Wan, T.; Li, S.; Beltran, D. G.; Schacht, A.; Zhang, L.; Becker, D. F.; Zhang, L. Structural Basis of Non-Canonical Transcriptional Regulation by the σA-Bound Iron-Sulfur Protein WhiB1 in M. Tuberculosis. Nucleic Acids Res. 2020, 48 (2), 501–516. https://doi.org/10.1093/nar/gkz1133.
(4) Wan, T.; Horová, M.; Beltran, D. G.; Li, S.; Wong, H.-X.; Zhang, L.-M. Structural Insights into the Functional Divergence of WhiB-like Proteins in Mycobacterium Tuberculosis. Mol. Cell 2021, 81 (14), 2887-2900.e5. https://doi.org/10.1016/j.molcel.2021.06.002.