Molecular Microbiology and Structural Biochemistry, Labex Ecofect, UMR 5086 CNRS/Université de Lyon, Lyon 69367, France.
Department of Medicine II/Molecular Biology, University Hospital Freiburg, Medical Center, University of Freiburg, Freiburg 79106, Germany.
Proc Natl Acad Sci U S A. 2021 Apr 27;118(17). doi: 10.1073/pnas.2022464118.
Viral hepatitis is growing into an epidemic illness, and it is urgent to neutralize the main culprit, hepatitis B virus (HBV), a small-enveloped retrotranscribing DNA virus. An intriguing observation in HB virion morphogenesis is that capsids with immature genomes are rarely enveloped and secreted. This prompted, in 1982, the postulate that a regulated conformation switch in the capsid triggers envelopment. Using solid-state NMR, we identified a stable alternative conformation of the capsid. The structural variations focus on the hydrophobic pocket of the core protein, a hot spot in capsid-envelope interactions. This structural switch is triggered by specific, high-affinity binding of a pocket factor. The conformational change induced by the binding is reminiscent of a maturation signal. This leads us to formulate the "synergistic double interaction" hypothesis, which explains the regulation of capsid envelopment and indicates a concept for therapeutic interference with HBV envelopment.
病毒性肝炎正在发展成为一种流行疾病，急需中和主要罪魁祸首乙型肝炎病毒 (HBV)，这是一种小包膜逆转录 DNA 病毒。在乙型肝炎病毒衣壳形态发生中一个有趣的观察结果是，具有不成熟基因组的衣壳很少被包膜和分泌。这促使人们在 1982 年提出假设，即衣壳中的调节构象转换触发包膜。我们使用固态 NMR 鉴定了衣壳的一种稳定的替代构象。结构变化集中在核心蛋白的疏水口袋上，这是衣壳-包膜相互作用的热点。这种结构转换由口袋因子的特异性高亲和力结合触发。结合诱导的构象变化让人联想到成熟信号。这使我们提出了“协同双重相互作用”假说，该假说解释了衣壳包膜的调节，并为治疗性干扰 HBV 包膜提供了一个概念。
