Structure of the Vif-binding Domain of the Antiviral Enzyme APOBEC3G

Nat Struct Mol Biol. 2015 Jun;22(6):485-91. doi: 10.1038/nsmb.3033. Epub 2015 May 18.

Abstract

The human APOBEC3G (A3G) DNA cytosine deaminase restricts and hypermutates DNA-based parasites including HIV-1. The viral infectivity factor (Vif) prevents restriction by triggering A3G degradation. Although the structure of the A3G catalytic domain is known, the structure of the N-terminal Vif-binding domain has proven more elusive. Here, we used evolution- and structure-guided mutagenesis to solubilize the Vif-binding domain of A3G, thus permitting structural determination by NMR spectroscopy. A smaller zinc-coordinating pocket and altered helical packing distinguish the structure from previous catalytic-domain structures and help to explain the reported inactivity of this domain. This soluble A3G N-terminal domain is bound by Vif; this enabled mutagenesis and biochemical experiments, which identified a unique Vif-interacting surface formed by the α1-β1, β2-α2 and β4-α4 loops. This structure sheds new light on the Vif-A3G interaction and provides critical information for future drug development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • APOBEC-3G Deaminase
  • Cytidine Deaminase / chemistry*
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism*
  • DNA Mutational Analysis
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Mapping
  • vif Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Mutant Proteins
  • vif Gene Products, Human Immunodeficiency Virus
  • vif protein, Human immunodeficiency virus 1
  • APOBEC-3G Deaminase
  • APOBEC3G protein, human
  • Cytidine Deaminase

Associated data

  • PDB/2MZZ