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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Published in:Communications biology 2022-02, Vol.5 (1), p.120-120, Article 120
Main Authors: Saridakis, Emmanuel, Vishwakarma, Rishi, Lai-Kee-Him, Josephine, Martin, Kevin, Simon, Isabelle, Cohen-Gonsaud, Martin, Coste, Franck, Bron, Patrick, Margeat, Emmanuel, Boudvillain, Marc
Format: Article
Language:English
Subjects:
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Adenosine triphosphatase
Antibiotics
Bacteriology
Bicozamycin
Biochemistry, Molecular Biology
Biology
Biomedical and Life Sciences
Conformation
DNA helicase
Genomes
Life Sciences
Methionine
Microbiology and Parasitology
Mycobacterium tuberculosis
Rho protein
Structural Biology
Transcription termination
Transcription termination factor RHO
Tuberculosis
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Summary: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