7u4a

Publication Abstract from PubMed

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.

Lifetime of ground conformational state determines the activity of structured RNA.,Thompson RD, Carbaugh DL, Nielsen JR, Witt CM, Faison EM, Meganck RM, Rangadurai A, Zhao B, Bonin JP, Nicely NI, Marzluff WF, Frank AT, Lazear HM, Zhang Q Nat Chem Biol. 2025 Feb 12. doi: 10.1038/s41589-025-01843-1. PMID:39939412^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.