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Structural basis for substrate binding and selection by human mitochondrial RNA polymerase

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  • Karl Herbine

    (Thomas Jefferson University)

  • Ashok R. Nayak

    (Thomas Jefferson University)

  • Dmitry Temiakov

    (Thomas Jefferson University)

Abstract

The mechanism by which RNAP selects cognate substrates and discriminates between deoxy and ribonucleotides is of fundamental importance to the fidelity of transcription. Here, we present cryo-EM structures of human mitochondrial transcription elongation complexes that reveal substrate ATP bound in Entry and Insertion Sites. In the Entry Site, the substrate binds along the O helix of the fingers domain of mtRNAP but does not interact with the templating DNA base. Interactions between RNAP and the triphosphate moiety of the NTP in the Entry Site ensure discrimination against nucleosides and their diphosphate and monophosphate derivatives but not against non-cognate rNTPs and dNTPs. Closing of the fingers domain over the catalytic site results in delivery of both the templating DNA base and the substrate into the Insertion Site and recruitment of the catalytic magnesium ions. The cryo-EM data also reveal a conformation adopted by mtRNAP to reject a non-cognate substrate from its active site. Our findings establish a structural basis for substrate binding and suggest a unified mechanism of NTP selection for single-subunit RNAPs.

Suggested Citation

  • Karl Herbine & Ashok R. Nayak & Dmitry Temiakov, 2024. "Structural basis for substrate binding and selection by human mitochondrial RNA polymerase," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50817-9
    DOI: 10.1038/s41467-024-50817-9
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    References listed on IDEAS

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    1. Joonas A. Jamsen & David D. Shock & Samuel H. Wilson, 2022. "Watching right and wrong nucleotide insertion captures hidden polymerase fidelity checkpoints," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Janne J. Mäkinen & Yeonoh Shin & Eeva Vieras & Pasi Virta & Mikko Metsä-Ketelä & Katsuhiko S. Murakami & Georgiy A. Belogurov, 2021. "The mechanism of the nucleo-sugar selection by multi-subunit RNA polymerases," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Sylvie Doublié & Stanley Tabor & Alexander M. Long & Charles C. Richardson & Tom Ellenberger, 1998. "Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 Å resolution," Nature, Nature, vol. 391(6664), pages 251-258, January.
    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. Rieke Ringel & Marina Sologub & Yaroslav I. Morozov & Dmitry Litonin & Patrick Cramer & Dmitry Temiakov, 2011. "Structure of human mitochondrial RNA polymerase," Nature, Nature, vol. 478(7368), pages 269-273, October.
    6. Nina A. Bonekamp & Bradley Peter & Hauke S. Hillen & Andrea Felser & Tim Bergbrede & Axel Choidas & Moritz Horn & Anke Unger & Raffaella Lucrezia & Ilian Atanassov & Xinping Li & Uwe Koch & Sascha Men, 2020. "Small-molecule inhibitors of human mitochondrial DNA transcription," Nature, Nature, vol. 588(7839), pages 712-716, December.
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