Hepatitis B Virus Capsids Have Diverse Structural Responses to Small-Molecule Ligands Bound to the Heteroaryldihydropyrimidine Pocket.

摘要: ABSTRACT Though the hepatitis B virus (HBV) core protein is an important participant in many aspects of viral life cycle, its best-characterized activity self-assembly into 240-monomer capsids. Small molecules that target (core allosteric modulators [CpAMs]) represent a promising antiviral strategy. To better understand structural basis CpAM mechanism, we determined crystal structure HBV capsid complex with HAP18. HAP18 accelerates assembly, increases protein-protein association more than 100-fold, and induces assembly nonicosahedral macrostructures. In preformed capsid, found at quasiequivalent subunit-subunit interfaces. detailed comparison to two other extant structures, find HAP18-capsid presents paradox. Whereas structures expanded diameter by up 10 A, caused only minor changes quaternary actually decreased ∼3 A. These results indicate CpAMs do not have single effect on structure. We suggest capsids present ensemble states can be trapped CpAMs, indicating for drug design. IMPORTANCE Hepatitis has multiple roles cycle—assembly, compartment reverse transcription, intracellular trafficking, nuclear functions—making it attractive target. Core (CpAMs) are experimental class antivirals bind protein. The most recognized they accelerate strengthen interactions between subunits. this study, observe CpAM-binding pocket conformations. compare cocrystallized different also affect ways. “breathes” crystallization. Understanding moving will aid design improve our understanding interaction environment.