Abstract
The single‐stranded DNA cytosine deaminase APOBEC3B (A3B) functions in innate immunity against viruses, but it is also strongly implicated in eliciting mutations in cancer genomes. Because of the critical role of A3B in promoting virus and tumor evolution, small molecule inhibitors are desirable. However, there is no reported structure for any of the APOBEC3‐family enzymes in complex with a small molecule bound in the active site, which hampers the development of small molecules targeting A3B. Here we report high‐resolution structures of an active A3B catalytic domain chimera with loop 7 residues exchanged with those from the corresponding region of APOBEC3G (A3G). The structures reveal novel open conformations lacking the catalytically essential zinc ion, with the highly conserved active site residues extensively rearranged. These inactive conformations are stabilized by 2‐pyrimidone or an iodide ion bound in the active site. Molecular dynamics simulations corroborate the remarkable plasticity of the engineered active site and identify key interactions that stabilize the native A3B active site. These data provide insights into A3B active site dynamics and suggest possible modes of its inhibition by small molecules, which would aid in rational design of selective A3B inhibitors for constraining virus and tumor evolution.
Highlights
The hallmark activity of the APOBEC family of enzymes is catalyzing a zinc ion-mediated hydrolytic deamination of 2'-deoxycytidine to 2'-deoxyuridine in single-strandedDNA [reviewed by Refs. 1,2]
The crystal structures of A3B-GL7 captured in distinct inactive conformations (Figure 1A-C and 2C), combined with molecular dynamics (MD) simulation results (Figure 6), highlight remarkable plasticity of the A3B active site and identify key interactions that stabilize the native A3B active site
Our studies suggest possible means by which small molecules could inhibit A3B activity
Summary
The hallmark activity of the APOBEC family of enzymes is catalyzing a zinc ion-mediated hydrolytic deamination of 2'-deoxycytidine to 2'-deoxyuridine in single-stranded (ss)DNA [reviewed by Refs. 1,2]. The hallmark activity of the APOBEC family of enzymes is catalyzing a zinc ion-mediated hydrolytic deamination of 2'-deoxycytidine to 2'-deoxyuridine in single-stranded (ss)DNA [reviewed by Refs. In addition to AID and APOBEC1, human cells have the potential to express up to seven different APOBEC3 (A3) enzymes (A3A-D, A3F-H). These enzymes have overlapping functions in providing innate immunity to viral infections with, for instance, A3D/F/ G/H capable of restricting the replication of the retrovirus HIV-1. Best characterized for roles in restricting retrovirus and retrotransposon replication (with obligate ssDNA intermediates), several family members have been implicated in the restriction of small and large double-stranded (ds)DNA tumor viruses.
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