Structural and functional analyses of hepatitis B virus X protein BH3-like domain and Bcl-xL interaction
Structural and functional analyses of hepatitis B virus X protein BH3-like domain and Bcl-xL interaction
复制标题
乙型肝炎病毒X蛋白BH3样结构域和Bcl-xL相互作用的结构和功能分析
DOI：
10.1038/s41467-019-11173-1
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发表时间：
2019-07-19
影响因子：
16.6
通讯作者：
Yuan, Y. Adam
中科院分区：
文献类型：
--
作者：
Zhang, Tian-Ying;Chen, Hong-Ying;Yuan, Y. Adam
B型肝炎病毒（HBV）X蛋白（HBx）通过其BH 3样基序与抗凋亡Bcl-2和Bcl-xL蛋白相互作用以促进HBV复制和细胞毒性。本文报道了HBx BH 3-like motif与Bcl-xL复合物的晶体结构，其中BH 3-like motif采用短α-螺旋通过其非经典Trp 120残基和保守Leu 123残基依偎到Bcl-xL的疏水口袋中。该结合口袋与具有促凋亡BH 3-only蛋白的Bcl-xL结构中的典型BH 3-only结合口袋相距约2 μ m。改变HBx中Trp 120和Leu 123的突变损害了其与Bcl-xL的体外结合和体内HBV复制，证实了该基序对HBV的重要性。HBx BH 3样肽HBx-aa 113 -135从HBx无效的HBV复制子恢复HBV复制，而较短的肽HBx-aa 118 -127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。
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.