Lifetime of ground conformational state determines the activity of structured RNA
Open accessPublished version of a preprint
Abstract
Biomolecules continually sample alternative conformations. Consequently, even the most energetically favored ground conformational state has a finite lifetime. Here, we show that, in addition to the three-dimensional (3D) structure, the lifetime of a ground conformational state determines its biological activity. Using hydrogen-deuterium exchange nuclear magnetic resonance spectroscopy, we found that Zika virus exoribonuclease-resistant RNA (xrRNA) encodes a ground conformational state with a lifetime that is ~10 5-10 7 longer than that of canonical base pairs. Mutations that shorten the apparent lifetime of the ground state without affecting its 3D structure decreased exoribonuclease resistance in vitro and impaired virus replication in cells. Additionally, we observed this exceptionally long-lived ground state in xrRNAs from diverse infectious mosquito-borne flaviviruses. These results demonstrate the biological importance of the lifetime of a preorganized ground state and further suggest that elucidating the lifetimes of dominant 3D structures of biomolecules may be crucial for understanding their behaviors and functions.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Akiyama, B. M., Laurence, H. M., Massey, A. R., Costantino, D. A., Xie, X., Yang, Y., Shi, P.-Y., Nix, J. C., Beckham, J. D., & Kieft, J. S. (2016) · Science · doi:10.1126/science.aah3963 · Cited by 245 · see citing works
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- Authors
- Thompson, R. D., Carbaugh, D. L., Nielsen, J. R., Witt, C. M., Faison, E. M., Meganck, R. M., Rangadurai, A., Zhao, B., Bonin, J. P., Nicely, N. I., Marzluff, W. F., Frank, A. T., Lazear, H. M., & Zhang, Q.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Michigan (US)
- Duke University (US)
- Corresponding author
- Frank, Aaron T.
- Lazear, Helen M.
- Zhang, Qi
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2025-02-12
- Volume
- 21
- Issue
- 7
- Pages
- 1021-1029
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC12202162
- OpenAlex
- W4407416054
- Cited by
- 7
- References
- 2
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 1
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- PubMed Central (submittedVersion, cc-by)
- UNC Libraries
- Funders
- U.S. Department of Energy (Contract No. W-31-109-Eng-38, W - 31 - 109 - Eng - 38)
- U.S. Department of Health and Human Services (R01GM114432)
- Burroughs Wellcome Fund
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (AI007419)
- National Institutes of Health
- Office of Science (W-31-109-ENG-38)
- University of North Carolina at Chapel Hill (P30-CA016086, R01 GM114432)
- National Cancer Institute (P30CA008748, T32CA244125, P30CA016086)
- National Institute of General Medical Sciences (R01GM114432)
- National Institute of Allergy and Infectious Diseases (R01AI139512, T32AI007419)
- Basic Energy Sciences (W-31-109-Eng38)
- School of Medicine, University of North Carolina at Chapel Hill
- Argonne National Laboratory
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- RNA conformational dynamics, RNA stability, hydrogen-deuterium exchange, viral replication, RNA tertiary structure
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