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

Author

Listed:
  • Tian-Ying Zhang

    (Xiamen University
    Xiamen University)

  • Hong-Ying Chen

    (National University of Singapore (Suzhou) Research Institute)

  • Jia-Li Cao

    (Xiamen University
    Xiamen University)

  • Hua-Long Xiong

    (Xiamen University
    Xiamen University)

  • Xiao-Bing Mo

    (National University of Singapore (Suzhou) Research Institute)

  • Tian-Liang Li

    (University of Colorado)

  • Xiao-Zhen Kang

    (Xiamen University
    Xiamen University)

  • Jing-Hua Zhao

    (Xiamen University
    Xiamen University)

  • Bo Yin

    (National University of Singapore (Suzhou) Research Institute)

  • Xiang Zhao

    (Tsinghua University)

  • Cheng-Hao Huang

    (Xiamen University
    Xiamen University)

  • Quan Yuan

    (Xiamen University
    Xiamen University)

  • Ding Xue

    (University of Colorado
    Tsinghua University)

  • Ning-Shao Xia

    (Xiamen University
    Xiamen University)

  • Y. Adam Yuan

    (National University of Singapore (Suzhou) Research Institute
    National University of Singapore)

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.

Suggested Citation

  • 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-Sha, 2019. "Structural and functional analyses of hepatitis B virus X protein BH3-like domain and Bcl-xL interaction," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11173-1
    DOI: 10.1038/s41467-019-11173-1
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    Cited by:

    1. Wei Liu & Qiyan Yao & Xiaonan Su & Yafang Deng & Mo Yang & Bo Peng & Fan Zhao & Chao Du & Xiulan Zhang & Jinsong Zhu & Daliang Wang & Wenhui Li & Haitao Li, 2023. "Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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