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Article Dans Une Revue Communications Biology Année : 2022

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

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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.
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hal-03563179 , version 1 (03-06-2022)

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Emmanuel Saridakis, Rishi Vishwakarma, Josephine Lai-Kee-Him, Kevin Martin, Isabelle Simon, et al.. Cryo-EM structure of transcription termination factor Rho from Mycobacterium tuberculosis reveals bicyclomycin resistance mechanism. Communications Biology, 2022, 5 (1), pp.120. ⟨10.1038/s42003-022-03069-6⟩. ⟨hal-03563179⟩
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