Small-Angle X-ray Scattering Models of APOBEC3B Catalytic Domain in a Complex with a Single-Stranded DNA Inhibitor

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2021 Mar 6

PMID 33673243

Citations 5

Authors

Fareeda M Barzak

Timothy M Ryan

Maksim V Kvach

Harikrishnan M Kurup

Hideki Aihara

Reuben S Harris

Vyacheslav V Filichev

Elena Harjes

Geoffrey B Jameson

Affiliations

Soon will be listed here.

Abstract

In normal cells APOBEC3 (A3A-A3H) enzymes as part of the innate immune system deaminate cytosine to uracil on single-stranded DNA (ssDNA) to scramble DNA in order to give protection against a range of exogenous retroviruses, DNA-based parasites, and endogenous retroelements. However, some viruses and cancer cells use these enzymes, especially A3A and A3B, to escape the adaptive immune response and thereby lead to the evolution of drug resistance. We have synthesized first-in-class inhibitors featuring modified ssDNA. We present models based on small-angle X-ray scattering (SAXS) data that (1) confirm that the mode of binding of inhibitor to an active A3B C-terminal domain construct in the solution state is the same as the mode of binding substrate to inactive mutants of A3A and A3B revealed in X-ray crystal structures and (2) give insight into the disulfide-linked inactive dimer formed under the oxidizing conditions of purification.

Citing Articles

Clinical Implications of APOBEC3-Mediated Mutagenesis in Breast Cancer.

Roelofs P, Martens J, Harris R, Span P Clin Cancer Res. 2022; 29(9):1658-1669.

PMID: 36478188 PMC: 10159886. DOI: 10.1158/1078-0432.CCR-22-2861.

Exploring ABOBEC3A and APOBEC3B substrate specificity and their role in HPV positive head and neck cancer.

Papini C, Wang Z, Kudalkar S, Schrank T, Tang S, Sasaki T iScience. 2022; 25(10):105077.

PMID: 36164654 PMC: 9508485. DOI: 10.1016/j.isci.2022.105077.

Small-Angle X-ray Scattering (SAXS) Measurements of APOBEC3G Provide Structural Basis for Binding of Single-Stranded DNA and Processivity.

Barzak F, Ryan T, Mohammadzadeh N, Harjes S, Kvach M, Kurup H Viruses. 2022; 14(9).

PMID: 36146779 PMC: 9505750. DOI: 10.3390/v14091974.

The current toolbox for APOBEC drug discovery.

Grillo M, Jones K, Carpenter M, Harris R, Harki D Trends Pharmacol Sci. 2022; 43(5):362-377.

PMID: 35272863 PMC: 9018551. DOI: 10.1016/j.tips.2022.02.007.

Special Issue "APOBECs and Virus Restriction".

Chelico L Viruses. 2021; 13(8).

PMID: 34452478 PMC: 8402836. DOI: 10.3390/v13081613.

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