亚基-亚基接触的局部稳定导致乙型肝炎病毒衣壳的整体失稳

StephenW

    Format: Abstract

Send to
ACS Chem Biol. 2020 May 5. doi: 10.1021/acschembio.0c00320. [Epub ahead of print]
Local stabilization of subunit-subunit contacts causes global destabilization of Hepatitis B virus capsids.
Schlicksup CJ, Laughlin P, Dunkelbarger S, Wang JC, Zlotnick A.
Abstract

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, which 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 pre-formed 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 inter-subunit 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.

PMID:
    32369333
DOI:
    10.1021/acschembio.0c00320

StephenW

格式：摘要

发送至
ACS化学生物学。 2020年5月5日。doi：10.1021 / acschembio.0c00320。 [Epub提前发布]
亚基-亚基接触的局部稳定导致乙型肝炎病毒衣壳的整体失稳。
Schlicksup CJ，Laughlin P，Dunkelbarger S，Wang JC，Zlotnick A.
抽象

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（一种二苯并噻氮平）的行为，它与乙型肝炎病毒（HBV）的衣壳蛋白发生特异性相互作用。我们发现DBT1稳定蛋白质间相互作用，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的组装，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。使用冷冻电子显微镜，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。这些结果表明，DBT1可以通过增加掩埋表面积来支持组装，但通过促进不对称性诱导结构缺陷，可以诱导亚稳态衣壳的分解。

PMID：
    32369333
DOI：
    10.1021 / acschembio.0c00320

StephenW

https://www.biorxiv.org/content/10.1101/2020.01.24.918904v1.full

newchinabok

今年欧美乙肝研发都熄火了