Cryo-EM structure of the transcription termination factor Rho from Mycobacterium tuberculosis reveals mechanism of resistance to bicyclomycin
Cryo-EM structure of the transcription termination factor Rho from Mycobacterium tuberculosis reveals mechanism of resistance to bicyclomycin
ABSTRACT 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 [MtbRho] factor displays poor NTPase and helicase activities, and resistance to the natural Rho inhibitor bicyclomycin [BCM] that remain unexplained. Here, we address these unusual features by solving the cryo-EM structure of MtbRho at 3.3 ? resolution, providing a new framework for future antibiotic development. The MtbRho hexamer is poised into a pre-catalytic, open-ringed state wherein specific contacts stabilize ATP in intersubunit ATPase pockets, thereby explaining the cofactor preference of MtbRho. 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.
Simon Isabelle、Cohen-Gonsaud Martin、Bron Patrick、Margeat Emmanuel、Coste Franck、Saridakis Emmanuel、Martin Kevin、Lai-Kee-Him Josephine、Vishwakarma Rishi、Boudvillain Marc
ED 549, Sant¨|, Sciences Biologiques & Chimie du Vivant, Universit¨| d?ˉOrl¨|ans||Centre de Biophysique Mol¨|culaire, CNRS UPR4301 Universit¨| d?ˉOrl¨|ansCentre de Biologie Structurale, INSERM, CNRS, Universit¨| de MontpellierCentre de Biologie Structurale, INSERM, CNRS, Universit¨| de MontpellierCentre de Biologie Structurale, INSERM, CNRS, Universit¨| de MontpellierCentre de Biophysique Mol¨|culaire, CNRS UPR4301 Universit¨| d?ˉOrl¨|ansInstitute of Nanoscience and Nanotechnology, NCSR ?°Demokritos?±||Le Studium Loire Valley Institute for Advanced StudiesCentre de Biologie Structurale, INSERM, CNRS, Universit¨| de MontpellierCentre de Biologie Structurale, INSERM, CNRS, Universit¨| de MontpellierCentre de Biologie Structurale, INSERM, CNRS, Universit¨| de Montpellier||Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University ParkLe Studium Loire Valley Institute for Advanced Studies||Centre de Biophysique Mol¨|culaire, CNRS UPR4301 Universit¨| d?ˉOrl¨|ans
基础医学生物科学研究方法、生物科学研究技术分子生物学
Simon Isabelle,Cohen-Gonsaud Martin,Bron Patrick,Margeat Emmanuel,Coste Franck,Saridakis Emmanuel,Martin Kevin,Lai-Kee-Him Josephine,Vishwakarma Rishi,Boudvillain Marc.Cryo-EM structure of the transcription termination factor Rho from Mycobacterium tuberculosis reveals mechanism of resistance to bicyclomycin[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2021.06.25.449899.点此复制
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