乙型肝炎病毒衣壳蛋白中的装配激活位点也可触发拆卸。

StephenW

An Assembly-activating Site in the Hepatitis B Virus Capsid Protein can also Trigger Disassembly.
Qazi S, Schlicksup CJ, Rittichier J, VanNieuwenhze MS, Zlotnick A.
Abstract

The Hepatitis B Virus (HBV) core protein homodimers self-assemble to form an icosahedral capsid that packages the viral genome. Disassembly occurs in the nuclear basket to release the mature genome to the nucleus. Small molecules have been developed that bind to a pocket at the inter-dimer interface to accelerate assembly and strengthen interactions between subunits; these are under development as antiviral agents. Here, we explore the role of the dimer-dimer interface by mutating sites in the pocket to cysteine and examining the effect of covalently linking small molecules to them. We find that ligands bound to the pocket may trigger capsid disassembly in a dose-dependent manner. This result indicates that, at least transiently, the pocket adopts a destabilizing conformation. We speculate that this pocket also plays a role in virus disassembly and genome release by binding ligands that are incompatible with virus stability, "unwanted guests". Investigating protein-protein interactions, especially large protein polymers, offers new and unique challenges. By using an engineered addressable thiol, we provide a means to examine the effects of modifying an interface without requiring drug-like properties for the ligand.

PMID:
    29920071
DOI:
    10.1021/acschembio.8b00283

StephenW

乙型肝炎病毒衣壳蛋白中的装配激活位点也可触发拆卸。
Qazi S，Schlicksup CJ，Rittichier J，VanNieuwenhze MS，Zlotnick A.
抽象

乙型肝炎病毒（HBV）核心蛋白同源二聚体自组装以形成包装病毒基因组的二十面体衣壳。拆卸发生在核篮中以将成熟的基因组释放到细胞核中。已经开发出小分子，其在二聚体间界面处结合口袋以加速装配并增强亚基之间的相互作用;这些正在开发中作为抗病毒剂。在这里，我们通过将口袋中的位点突变为半胱氨酸并检查共价连接小分子对它们的影响来探索二聚体 - 二聚体界面的作用。我们发现绑定到口袋的配体可能以剂量依赖性方式触发衣壳分解。该结果表明，至少暂时地，口袋采取不稳定构象。我们推测这个口袋也通过结合与病毒稳定性不相容的配体“不需要的客人”在病毒分解和基因组释放中起作用。研究蛋白质 - 蛋白质相互作用，尤其是大蛋白质聚合物，提供了新的独特挑战。通过使用工程化的可寻址巯基，我们提供了一种方法来检查修饰界面的效果，而不需要配体的药物样性质。

结论：
    29920071
DOI：
    10.1021 / acschembio.8b00283