Cryo-EM structure of transcription termination factor Rho from Mycobacterium tuberculosis reveals bicyclomycin resistance mechanism

The bacterial Rho factor is a ring-shaped motor triggering genome-wide transcription termination and R-loop dissociation. Rho is essential in many species, including in Mycobacterium tuberculosis where rho gene inactivation leads to rapid death. Yet, the M. tuberculosis Rho [ Mtb Rho] factor display...

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Veröffentlicht in:Communications biology 2022-02, Vol.5 (1), p.120-120, Article 120
Hauptverfasser: Saridakis, Emmanuel, Vishwakarma, Rishi, Lai-Kee-Him, Josephine, Martin, Kevin, Simon, Isabelle, Cohen-Gonsaud, Martin, Coste, Franck, Bron, Patrick, Margeat, Emmanuel, Boudvillain, Marc
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Sprache:eng
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Zusammenfassung:The bacterial Rho factor is a ring-shaped motor triggering genome-wide transcription termination and R-loop dissociation. Rho is essential in many species, including in Mycobacterium tuberculosis where rho gene inactivation leads to rapid death. Yet, the M. tuberculosis Rho [ Mtb Rho] factor displays poor NTPase and helicase activities, and resistance to the natural Rho inhibitor bicyclomycin [BCM] that remain unexplained. To address these issues, we solved the cryo-EM structure of Mtb Rho at 3.3 Å resolution. The Mtb Rho hexamer is poised into a pre-catalytic, open-ring state wherein specific contacts stabilize ATP in intersubunit ATPase pockets, thereby explaining the cofactor preference of Mtb Rho. We reveal a leucine-to-methionine substitution that creates a steric bulk in BCM binding cavities near the positions of ATP γ-phosphates, and confers resistance to BCM at the expense of motor efficiency. Our work contributes to explain the unusual features of Mtb Rho and provides a framework for future antibiotic development. Cryo-EM shows that M. tuberculosis Rho-factor adopts an open, ring-shaped hexamer conformation and a steric bulk in the cavity for bicyclomycin binding, which explains resistance to the antibiotic.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-022-03069-6