乙型肝炎病毒 X 蛋白 BH3 样结构域与 Bcl-xL 相互作用的结构与功能分析。
Structural and functional analyses of hepatitis B virus X protein BH3-like domain and Bcl-xL interaction.
机构信息
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health and School of Life Sciences, Xiamen University, 361102, Xiamen, China.
National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health and School of Life Sciences, Xiamen University, 361102, Xiamen, China.
出版信息
Nat Commun. 2019 Jul 19;10(1):3192. doi: 10.1038/s41467-019-11173-1.
Hepatitis B virus (HBV) X protein, HBx, interacts with anti-apoptotic Bcl-2 and Bcl-xL proteins through its BH3-like motif to promote HBV replication and cytotoxicity. Here we report the crystal structure of HBx BH3-like motif in complex with Bcl-xL where the BH3-like motif adopts a short α-helix to snuggle into a hydrophobic pocket in Bcl-xL via its noncanonical Trp120 residue and conserved Leu123 residue. This binding pocket is ~2 Å away from the canonical BH3-only binding pocket in structures of Bcl-xL with proapoptotic BH3-only proteins. Mutations altering Trp120 and Leu123 in HBx impair its binding to Bcl-xL in vitro and HBV replication in vivo, confirming the importance of this motif to HBV. A HBx BH3-like peptide, HBx-aa113-135, restores HBV replication from a HBx-null HBV replicon, while a shorter peptide, HBx-aa118-127, inhibits HBV replication. These results provide crucial structural and functional insights into drug designs for inhibiting HBV replication and treating HBV patients.
乙型肝炎病毒（HBV）X 蛋白（HBx）通过其 BH3 样结构域与抗凋亡 Bcl-2 和 Bcl-xL 蛋白相互作用，促进 HBV 复制和细胞毒性。在这里，我们报告了 HBx BH3 样结构域与 Bcl-xL 复合物的晶体结构，其中 BH3 样结构域采用短 α-螺旋结构，通过其非典型的色氨酸 120 残基和保守的亮氨酸 123 残基，紧贴在 Bcl-xL 的疏水性口袋中。该结合口袋距离 Bcl-xL 与促凋亡 BH3 仅蛋白结构中的典型 BH3 仅结合口袋约 2Å。改变 HBx 中色氨酸 120 和亮氨酸 123 的突变会损害其在体外与 Bcl-xL 的结合以及体内 HBV 的复制，证实了该结构域对 HBV 的重要性。HBx BH3 样肽 HBx-aa113-135 可恢复 HBx 缺失型 HBV 复制子中的 HBV 复制，而较短的肽 HBx-aa118-127 则抑制 HBV 复制。这些结果为抑制 HBV 复制和治疗 HBV 患者的药物设计提供了重要的结构和功能见解。
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