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High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein

2015; National Academy of Sciences; Volume: 112; Issue: 49 Linguagem: Inglês

10.1073/pnas.1513803112

1091-6490

Klaus Klumpp, Angela M. Lam, Christine Lukacs, Robert Vogel, Suping Ren, Christine Espiritu, Ruth Baydo, Kateri Atkins, Jan Abendroth, Guochun Liao, Andrey Efimov, George D. Hartman, Osvaldo Flores,

Biochemical and Molecular Research

The hepatitis B virus (HBV) core protein is essential for HBV replication and an important target for antiviral drug discovery. We report the first, to our knowledge, high-resolution crystal structure of an antiviral compound bound to the HBV core protein. The compound NVR-010-001-E2 can induce assembly of the HBV core wild-type and Y132A mutant proteins and thermostabilize the proteins with a Tm increase of more than 10 °C. NVR-010-001-E2 binds at the dimer-dimer interface of the core proteins, forms a new interaction surface promoting protein-protein interaction, induces protein assembly, and increases stability. The impact of naturally occurring core protein mutations on antiviral activity correlates with NVR-010-001-E2 binding interactions determined by crystallography. The crystal structure provides understanding of a drug efficacy mechanism related to the induction and stabilization of protein-protein interactions and enables structure-guided design to improve antiviral potency and drug-like properties.