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Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA

Author

Listed:
  • Atanu Maiti

    (Frederick National Laboratory for Cancer Research)

  • Wazo Myint

    (Frederick National Laboratory for Cancer Research)

  • Tapan Kanai

    (Frederick National Laboratory for Cancer Research)

  • Krista Delviks-Frankenberry

    (National Cancer Institute at Frederick)

  • Christina Sierra Rodriguez

    (Frederick National Laboratory for Cancer Research)

  • Vinay K. Pathak

    (National Cancer Institute at Frederick)

  • Celia A. Schiffer

    (University of Massachusetts Medical School)

  • Hiroshi Matsuo

    (Frederick National Laboratory for Cancer Research)

Abstract

The human APOBEC3G protein is a cytidine deaminase that generates cytidine to deoxy-uridine mutations in single-stranded DNA (ssDNA), and capable of restricting replication of HIV-1 by generating mutations in viral genome. The mechanism by which APOBEC3G specifically deaminates 5′-CC motifs has remained elusive since structural studies have been hampered due to apparently weak ssDNA binding of the catalytic domain of APOBEC3G. We overcame the problem by generating a highly active variant with higher ssDNA affinity. Here, we present the crystal structure of this variant complexed with a ssDNA substrate at 1.86 Å resolution. This structure reveals atomic-level interactions by which APOBEC3G recognizes a functionally-relevant 5′-TCCCA sequence. This complex also reveals a key role of W211 in substrate recognition, implicating a similar recognition in activation-induced cytidine deaminase (AID) with a conserved tryptophan.

Suggested Citation

  • Atanu Maiti & Wazo Myint & Tapan Kanai & Krista Delviks-Frankenberry & Christina Sierra Rodriguez & Vinay K. Pathak & Celia A. Schiffer & Hiroshi Matsuo, 2018. "Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04872-8
    DOI: 10.1038/s41467-018-04872-8
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    Cited by:

    1. Atanu Maiti & Adam K. Hedger & Wazo Myint & Vanivilasini Balachandran & Jonathan K. Watts & Celia A. Schiffer & Hiroshi Matsuo, 2022. "Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Stefan Harjes & Harikrishnan M. Kurup & Amanda E. Rieffer & Maitsetseg Bayarjargal & Jana Filitcheva & Yongdong Su & Tracy K. Hale & Vyacheslav V. Filichev & Elena Harjes & Reuben S. Harris & Geoffrey, 2023. "Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Qian Wang & Jie Yang & Zhicheng Zhong & Jeffrey A. Vanegas & Xue Gao & Anatoly B. Kolomeisky, 2021. "A general theoretical framework to design base editors with reduced bystander effects," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    4. Ambrocio Sanchez & Pedro Ortega & Ramin Sakhtemani & Lavanya Manjunath & Sunwoo Oh & Elodie Bournique & Alexandrea Becker & Kyumin Kim & Cameron Durfee & Nuri Alpay Temiz & Xiaojiang S. Chen & Reuben , 2024. "Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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