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Structural basis for substrate loading in bacterial RNA polymerase

Author

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  • Dmitry G. Vassylyev

    (University of Alabama at Birmingham, Schools of Medicine and Dentistry, 402B Kaul Genetics Building, 720 20th Street South, Birmingham, Alabama 35294, USA)

  • Marina N. Vassylyeva

    (University of Alabama at Birmingham, Schools of Medicine and Dentistry, 402B Kaul Genetics Building, 720 20th Street South, Birmingham, Alabama 35294, USA)

  • Jinwei Zhang

    (Department of Biomolecular Chemistry,)

  • Murali Palangat

    (Department of Biochemistry and,)

  • Irina Artsimovitch

    (The Ohio State University, 484 West 12th Avenue, Columbus, Ohio 43210, USA)

  • Robert Landick

    (Department of Biochemistry and,
    University of Wisconsin, Madison, Wisconsin 53706, USA)

Abstract

The mechanism of substrate loading in multisubunit RNA polymerase is crucial for understanding the general principles of transcription yet remains hotly debated. Here we report the 3.0-Å resolution structures of the Thermus thermophilus elongation complex (EC) with a non-hydrolysable substrate analogue, adenosine-5′-[(α,β)-methyleno]-triphosphate (AMPcPP), and with AMPcPP plus the inhibitor streptolydigin. In the EC/AMPcPP structure, the substrate binds to the active (‘insertion’) site closed through refolding of the trigger loop (TL) into two α-helices. In contrast, the EC/AMPcPP/streptolydigin structure reveals an inactive (‘preinsertion’) substrate configuration stabilized by streptolydigin-induced displacement of the TL. Our structural and biochemical data suggest that refolding of the TL is vital for catalysis and have three main implications. First, despite differences in the details, the two-step preinsertion/insertion mechanism of substrate loading may be universal for all RNA polymerases. Second, freezing of the preinsertion state is an attractive target for the design of novel antibiotics. Last, the TL emerges as a prominent target whose refolding can be modulated by regulatory factors.

Suggested Citation

  • Dmitry G. Vassylyev & Marina N. Vassylyeva & Jinwei Zhang & Murali Palangat & Irina Artsimovitch & Robert Landick, 2007. "Structural basis for substrate loading in bacterial RNA polymerase," Nature, Nature, vol. 448(7150), pages 163-168, July.
  • Handle: RePEc:nat:nature:v:448:y:2007:i:7150:d:10.1038_nature05931
    DOI: 10.1038/nature05931
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    Cited by:

    1. Juntaek Oh & Zelin Shan & Shuichi Hoshika & Jun Xu & Jenny Chong & Steven A. Benner & Dmitry Lyumkis & Dong Wang, 2023. "A unified Watson-Crick geometry drives transcription of six-letter expanded DNA alphabets by E. coli RNA polymerase," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Lin-Tai Da & Fátima Pardo Avila & Dong Wang & Xuhui Huang, 2013. "A Two-State Model for the Dynamics of the Pyrophosphate Ion Release in Bacterial RNA Polymerase," PLOS Computational Biology, Public Library of Science, vol. 9(4), pages 1-9, April.
    3. Charles Bou-Nader & Ankur Bothra & David N. Garboczi & Stephen H. Leppla & Jinwei Zhang, 2022. "Structural basis of R-loop recognition by the S9.6 monoclonal antibody," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Juntaek Oh & Michiko Kimoto & Haoqing Xu & Jenny Chong & Ichiro Hirao & Dong Wang, 2023. "Structural basis of transcription recognition of a hydrophobic unnatural base pair by T7 RNA polymerase," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    5. Anastasiia Chaban & Leonid Minakhin & Ekaterina Goldobina & Brain Bae & Yue Hao & Sergei Borukhov & Leena Putzeys & Maarten Boon & Florian Kabinger & Rob Lavigne & Kira S. Makarova & Eugene V. Koonin , 2024. "Tail-tape-fused virion and non-virion RNA polymerases of a thermophilic virus with an extremely long tail," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Claire Chung & Bert M. Verheijen & Zoe Navapanich & Eric G. McGann & Sarah Shemtov & Guan-Ju Lai & Payal Arora & Atif Towheed & Suraiya Haroon & Agnes Holczbauer & Sharon Chang & Zarko Manojlovic & St, 2023. "Evolutionary conservation of the fidelity of transcription," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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