Structural and functional analyses of hepatitis B virus X protein BH3-like domain and Bcl-xL interaction

Tian-Ying Zhang, Hong-Ying Chen, Jia-Li Cao, Hua-Long Xiong, Xiao-Bing Mo, Tian-Liang Li, Xiao-Zhen Kang, Jing-Hua Zhao, Bo Yin, Xiang Zhao, Cheng-Hao Huang, Quan Yuan (), Ding Xue (), Ning-Shao Xia () and Y. Adam Yuan
Additional contact information
Tian-Ying Zhang: Xiamen University
Hong-Ying Chen: National University of Singapore (Suzhou) Research Institute
Jia-Li Cao: Xiamen University
Hua-Long Xiong: Xiamen University
Xiao-Bing Mo: National University of Singapore (Suzhou) Research Institute
Tian-Liang Li: University of Colorado
Xiao-Zhen Kang: Xiamen University
Jing-Hua Zhao: Xiamen University
Bo Yin: National University of Singapore (Suzhou) Research Institute
Xiang Zhao: Tsinghua University
Cheng-Hao Huang: Xiamen University
Quan Yuan: Xiamen University
Ding Xue: University of Colorado
Ning-Shao Xia: Xiamen University
Y. Adam Yuan: National University of Singapore (Suzhou) Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11173-1

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