Conformational dynamics of the hepatitis B virus pre-genomic RNA on multiple time scales: implications for viral replication

Published

September 30, 2022

Author(s)

Lucasz T. Olenginski, Wojciech K. Kasprzak, Christina Bergonzo, Bruce A. Shapiro, Theodore Kwaku Dayie

Abstract

HBV replication is initiated by the binding of polymerase (P) to epsilon (ε), a 61 nucleotide (nt) cis -acting regulatory stem-loop RNA located at the 5′-end of the pregenomic RNA (pgRNA). This interaction triggers protein-primed reverse transcription and pgRNA packaging and is therefore an attractive therapeutic target. Our recent nuclear magnetic resonance (NMR) structure of ε provides a useful starting point toward a detailed understanding of HBV replication, and hints at the functional importance of ε dynamics. Here, we present a detailed description of ε motions on the picosecond-to-nanosecond and microsecond-to-millisecond time scales by NMR spin relaxation and relaxation dispersion, respectively. We also carried out molecular dynamics simulations to provide additional insight into ε conformational dynamics. These data outline a series of complex motions on multiple time scales within ε. Moreover, these motions occur in mostly conserved nucleotides from structural regions (i.e., priming loop, pseudo-triloop, and U43 bulge) that biochemical and mutational studies have shown to be essential for P binding, protein-priming, pgRNA packaging, and DNA synthesis. Taken together, our work strongly implicates RNA dynamics as an integral feature that governs HBV replication.

Citation

Journal of Molecular Biology

Volume

434

Pub Type

Journals

Download Paper

https://doi.org/10.1016/j.jmb.2022.167633

Local Download

Keywords

hepatitis B virus, viral replication, dynamics, NMR spectroscopy, conformational selection

Citation

Olenginski, L. , Kasprzak, W. , Bergonzo, C. , Shapiro, B. and Dayie, T. (2022), Conformational dynamics of the hepatitis B virus pre-genomic RNA on multiple time scales: implications for viral replication, Journal of Molecular Biology, [online], https://doi.org/10.1016/j.jmb.2022.167633, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=934234 (Accessed May 4, 2024)