5E0I

Crystal structure of the HBV capsid Y132A mutant (VCID 8772) in complex with NVR10-001E2 at 1.95A resolution

Summary for 5E0I

• Entry DOI: 10.2210/pdb5e0i/pdb
• Descriptor: Capsid protein, methyl 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-ylmethyl)-2-(1,3-thiazol-2-yl)pyrimidine-5-carboxylate (3 entities in total)
• Functional Keywords: nvr10-001e2, viral protein
• Biological source: Hepatitis B virus genotype D subtype adw (HBV-D)
• Cellular location: Capsid protein: Virion: P03147
• Total number of polymer chains: 6
• Total formula weight: 109089.31

Authors

Lukacs, C.M.,Abendroth, J.,Klumpp, K. (deposition date: 2015-09-28, release date: 2015-12-09, Last modification date: 2024-11-13)

Primary citation

Klumpp, K.,Lam, A.M.,Lukacs, C.,Vogel, R.,Ren, S.,Espiritu, C.,Baydo, R.,Atkins, K.,Abendroth, J.,Liao, G.,Efimov, A.,Hartman, G.,Flores, O.A.
High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein.
Proc.Natl.Acad.Sci.USA, 112:15196-15201, 2015

PubMed Abstract: 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.

PubMed: 26598693
DOI: 10.1073/pnas.1513803112

Experimental method

X-RAY DIFFRACTION (1.95 Å)