Title

Structure of the Vif-binding domain of the antiviral enzyme APOBEC3G

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

2015-06-01

Document Type

Article

Subjects

Cytidine Deaminase; DNA Mutational Analysis; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Mutant Proteins; Protein Binding; Protein Conformation; Protein Interaction Mapping; vif Gene Products, Human Immunodeficiency Virus

Disciplines

Biochemistry | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology | Virology

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 alpha1-beta1, beta2-alpha2 and beta4-alpha4 loops. This structure sheds new light on the Vif-A3G interaction and provides critical information for future drug development.

DOI of Published Version

10.1038/nsmb.3033

Source

Nat Struct Mol Biol. 2015 Jun;22(6):485-91. doi: 10.1038/nsmb.3033. Epub 2015 May 18. Link to article on publisher's site

Journal/Book/Conference Title

Nature structural and molecular biology

Related Resources

Link to Article in PubMed

PubMed ID

25984970

Share

COinS