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An RNA excited conformational state at atomic resolution

Author

Listed:
  • Ainan Geng

    (Duke University School of Medicine)

  • Laura Ganser

    (Duke University School of Medicine
    Johns Hopkins University)

  • Rohit Roy

    (Duke University School of Medicine)

  • Honglue Shi

    (Duke University
    University of California)

  • Supriya Pratihar

    (Columbia University)

  • David A. Case

    (Rutgers University)

  • Hashim M. Al-Hashimi

    (Columbia University)

Abstract

Sparse and short-lived excited RNA conformational states are essential players in cell physiology, disease, and therapeutic development, yet determining their 3D structures remains challenging. Combining mutagenesis, NMR spectroscopy, and computational modeling, we determined the 3D structural ensemble formed by a short-lived (lifetime ~2.1 ms) lowly-populated (~0.4%) conformational state in HIV-1 TAR RNA. Through a strand register shift, the excited conformational state completely remodels the 3D structure of the ground state (RMSD from the ground state = 7.2 ± 0.9 Å), forming a surprisingly more ordered conformational ensemble rich in non-canonical mismatches. The structure impedes the formation of the motifs recognized by Tat and the super elongation complex, explaining why this alternative TAR conformation cannot activate HIV-1 transcription. The ability to determine the 3D structures of fleeting RNA states using the presented methodology holds great promise for our understanding of RNA biology, disease mechanisms, and the development of RNA-targeting therapeutics.

Suggested Citation

  • Ainan Geng & Laura Ganser & Rohit Roy & Honglue Shi & Supriya Pratihar & David A. Case & Hashim M. Al-Hashimi, 2023. "An RNA excited conformational state at atomic resolution," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43673-6
    DOI: 10.1038/s41467-023-43673-6
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    References listed on IDEAS

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