An RNA excited conformational state at atomic resolution

Ainan Geng, Laura Ganser, Rohit Roy, Honglue Shi, Supriya Pratihar, David A. Case and Hashim M. Al-Hashimi ()
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Ainan Geng: Duke University School of Medicine
Laura Ganser: Duke University School of Medicine
Rohit Roy: Duke University School of Medicine
Honglue Shi: Duke University
Supriya Pratihar: Columbia University
David A. Case: Rutgers University
Hashim M. Al-Hashimi: Columbia University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43673-6

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