High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein
High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein
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DOI：
10.1073/pnas.1513803112
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发表时间：
2015-12-08
影响因子：
11.1
通讯作者：
Flores, Osvaldo A.
中科院分区：
文献类型：
--
作者：
Klumpp, Klaus;Lam, Angela M.;Flores, Osvaldo A.
B型肝炎病毒（HBV）核心蛋白是HBV复制所必需的，并且是抗病毒药物发现的重要靶点。据我们所知，我们报告了第一个与HBV核心蛋白结合的抗病毒化合物的高分辨率晶体结构。化合物NVR-010-001-E2可以诱导HBV核心野生型和Y132 A突变蛋白的组装，并使蛋白质热稳定，T-m增加超过10 ℃。NVR-010-001-E2在核心蛋白的二聚体-二聚体界面结合，形成促进蛋白质-蛋白质相互作用的新的相互作用表面，诱导蛋白质组装并增加稳定性。天然存在的核心蛋白突变对抗病毒活性的影响与通过晶体学确定的NVR-010-001-E2结合相互作用相关。晶体结构提供了对与蛋白质-蛋白质相互作用的诱导和稳定相关的药物功效机制的理解，并使结构导向设计能够改善抗病毒效力和药物样性质。
The hepatitis B virus (HBV) core protein is essential for HBV replication and an important target for antiviral drug discovery. We report the first, to our knowledge, high-resolution crystal structure of an antiviral compound bound to the HBV core protein. The compound NVR-010-001-E2 can induce assembly of the HBV core wild-type and Y132A mutant proteins and thermostabilize the proteins with a T-m increase of more than 10 degrees C. NVR-010-001-E2 binds at the dimer-dimer interface of the core proteins, forms a new interaction surface promoting protein-protein interaction, induces protein assembly, and increases stability. The impact of naturally occurring core protein mutations on antiviral activity correlates with NVR-010-001-E2 binding interactions determined by crystallography. The crystal structure provides understanding of a drug efficacy mechanism related to the induction and stabilization of protein-protein interactions and enables structure-guided design to improve antiviral potency and drug-like properties.