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Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
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Structure of the DNA deaminase domain of the HIV-1 restriction factor APOBEC3G

Kuan-Ming Chen1, Elena Harjes, Phillip J Gross

  • 1Department of Biochemistry, Molecular Biology and Biophysics, [of Minnesota, Minneapolis, Minnesota 55455, USA.

Nature
|February 22, 2008
PubMed

Insights

The human APOBEC3G protein, an antiviral enzyme, has a newly determined structure. This structure reveals how it binds DNA to inhibit viruses like HIV-1.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Virology

Background:

  • APOBEC3G (apolipoprotein B messenger-RNA-editing enzyme, catalytic polypeptide-like 3G) is a human DNA deaminase with antiviral properties against retroviruses like HIV-1.
  • Its antiviral activity is often overcome by viral factors, such as HIV-1 Vif, which leads to APOBEC3G degradation.
  • APOBEC3G belongs to a family of polynucleotide cytosine deaminases, including APOBEC1 and AID, which have distinct physiological roles.

Purpose of the Study:

  • To determine the solution structure of the human APOBEC3G catalytic domain.
  • To elucidate the mechanism of DNA binding and catalysis by APOBEC3G.
  • To provide insights into the interactions of APOBEC3G with viral proteins like HIV-1 Vif.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy for solution structure determination.
  • DNA titration experiments using NMR.
  • Computational modeling.
  • Phylogenetic conservation analysis.
  • Escherichia coli-based enzyme activity assays.

Main Results:

  • The solution structure of the APOBEC3G catalytic domain was determined, revealing an arrangement of five alpha-helices over a five-beta-strand hydrophobic platform.
  • Two alpha-helices were identified as forming the zinc-coordinating active site.
  • A DNA-binding model was proposed, suggesting that positively charged residues on a 'brim' position the target cytosine for catalysis.
  • The structure and DNA-binding model were supported by NMR, computational modeling, phylogenetic data, and functional assays.

Conclusions:

  • The determined structure of the APOBEC3G catalytic domain provides a molecular basis for its DNA deaminase and antiviral activities.
  • The proposed DNA-binding model offers insights into how APOBEC3G recognizes and interacts with its DNA substrate.
  • Understanding the APOBEC3G structure can facilitate research into the functions of related family members and their interactions with viral proteins, potentially aiding in the development of antiviral strategies.

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