Structural insights of the conserved "priming loop" of hepatitis B virus pre-genomic RNA

Author:

LeBlanc, Regan M [ORCID]

Kasprzak,Wojciech

Longhini, Andrew P

Olenginski, Lukasz T

Abulwerdi, Fardokht

Ginocchio, Stefano

Shields, Brigit

Nyman, Julie

Svirydava, Maryia

Del Vecchio, Claudia

Ivanic,Joseph

Schneekloth,Jay

Shapiro, Bruce A

Dayie, Theodore Kwaku [ORCID]

Le Grice,Stuart
Author Address

Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA., Vertex Pharmaceuticals, Boston, MA, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA., Department of Molecular, Cell and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA., RNA Biology Laboratory, National Cancer Institute, Frederick, MD, USA., Department of Molecular Medicine, University of Padua, Padua, Italy., Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA.,

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 (e), located at the 5 39;-end of its pre-genomic RNA (pgRNA). Binding of polymerase to e 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. e 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 e 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.

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