Local Stabilization of Subunit-Subunit Contacts Causes Global Destabilization of Hepatitis B Virus Capsids.,ACS Chemical Biology

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Local Stabilization of Subunit-Subunit Contacts Causes Global Destabilization of Hepatitis B Virus Capsids.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-05-05 , DOI: 10.1021/acschembio.0c00320
Christopher John Schlicksup ₁ , Patrick Laughlin ₁ , Steven Dunkelbarger ₁ , Joseph Che-Yen Wang _{1,

2} , Adam Zlotnick ₁

Affiliation

Development of antiviral molecules that bind virion is a strategy that remains in its infancy, and the details of their mechanisms are poorly understood. Here we investigate the behavior of DBT1, a dibenzothiazepine that specifically interacts with the capsid protein of hepatitis B virus (HBV). We found that DBT1 stabilizes protein–protein interaction, accelerates capsid assembly, and can induce formation of aberrant particles. Paradoxically, DBT1 can cause preformed capsids to dissociate. These activities may lead to (i) assembly of empty and defective capsids, inhibiting formation of new virus, and (ii) disruption of mature viruses, which are metastable, to inhibit new infection. Using cryo-electron microscopy, we observed that DBT1 led to asymmetric capsids where well-defined DBT1 density was bound at all intersubunit contacts. These results suggest that DBT1 can support assembly by increasing buried surface area but induce disassembly of metastable capsids by favoring asymmetry to induce structural defects.

中文翻译：

亚基-亚基接触的局部稳定导致乙型肝炎病毒衣壳的整体不稳定。

结合病毒体的抗病毒分子的开发是一种仍处于婴儿期的策略，对其机理的细节了解甚少。在这里，我们研究了DBT1的行为，DBT1是一种与苯乙型肝炎病毒（HBV）的衣壳蛋白特异性相互作用的二苯并硫氮杂pine。我们发现DBT1可以稳定蛋白质之间的相互作用，加速衣壳装配，并可以诱导异常颗粒的形成。矛盾的是，DBT1可能导致预先形成的衣壳解离。这些活动可能导致（i）空的和有缺陷的衣壳组装，抑制新病毒的形成，以及（ii）破坏亚稳态的成熟病毒，从而抑制新的感染。使用低温电子显微镜，我们观察到DBT1导致不对称衣壳，其中明确定义的DBT1密度绑定在所有亚基间接触处。

更新日期：2020-06-19

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