Structural insights of the conserved "priming loop" of hepatitis B virus pre-genomic RNA. Issue 20 (29th November 2022)

• Record Type: Journal Article
• Authors: LeBlanc, Regan M.; Kasprzak, Wojciech K.; Longhini, Andrew P.; Olenginski, Lukasz T.; Abulwerdi, Fardokht; Ginocchio, Stefano; Shields, Brigit; Nyman, Julie; Svirydava, Maryia; Del Vecchio, Claudia; Ivanic, Joseph; Schneekloth, John S.; Shapiro, Bruce A.; Dayie, Theodore Kwaku; Le Grice, Stuart F. J.
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 40:Issue 20(2022)
• Page Start: 9761
• Page End: 9773
• Publication Date: 2022-11-29
• Subjects: Hepatitis B virus -- RNA structure -- RNA dynamics -- NMR spectroscopy -- small molecule screen -- SERM; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2021.1934544
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: Initiation of protein-primed (-) strand DNA synthesis in hepatitis B virus (HBV) requires interaction of the viral polymerase with a cis -acting regulatory signal, designated epsilon (ε), located at the 5′-end of its pre-genomic RNA (pgRNA). Binding of polymerase to ε is also necessary for pgRNA encapsidation. While the mechanistic basis of this interaction remains elusive, mutagenesis studies suggest its internal 6-nt "priming loop" provides an important structural contribution. ε might therefore be considered a promising target for small molecule interventions to complement current nucleoside-analog based anti-HBV therapies. An ideal prerequisite to any RNA-directed small molecule strategy would be a detailed structural description of this important element. Herein, we present a solution NMR structure for HBV ε which, in combination with molecular dynamics and docking simulations, reports on a flexible ligand "pocket", reminiscent of those observed in proteins. We also demonstrate the binding of the selective estrogen receptor modulators (SERMs) Raloxifene, Bazedoxifene, and a de novo derivative to the priming loop. Communicated by Ramaswamy H. Sarma