Small-angle x-ray scattering models of apobec3b catalytic domain in a complex with a single-stranded dna inhibitor

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 retroele-ments. 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.

Original languageEnglish (US)
Article number290
JournalViruses
Volume13
Issue number2
DOIs
StatePublished - Feb 12 2021

Bibliographical note

Funding Information:
V.V.F., E.H., G.B.J., and M.V.K. are grateful for the financial support provided by the Worldwide Cancer Research (grant 16-1197), Palmerston North Medical Research Foundation, Massey University Research Fund (MURF 2015, 7003 and RM20734) and School of Fundamental Sciences, Massey University. F.M.B. was a recipient of Massey University graduate PhD scholarship. We gratefully acknowledge the support of the New Zealand Synchrotron Group Ltd. for facilitating access to the Australian Synchrotron. The labs of H.A. and R.S.H. are supported in part by NCI P01 CA234228. RH is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished McKnight University Professor, and an Investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding Information:
Funding: V.V.F., E.H., G.B.J., and M.V.K. are grateful for the financial support provided by the Worldwide Cancer Research (grant 16-1197), Palmerston North Medical Research Foundation, Massey University Research Fund (MURF 2015, 7003 and RM20734) and School of Fundamental Sciences, Massey University. F.M.B. was a recipient of Massey University graduate PhD scholarship. We gratefully acknowledge the support of the New Zealand Synchrotron Group Ltd. for facilitating access to the Australian Synchrotron. The labs of H.A. and R.S.H. are supported in part by NCI P01 CA234228. RH is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished McKnight University Professor, and an Investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • APOBEC
  • APOBEC inhibitors
  • APOBEC3
  • APOBEC3B
  • Cancer evolution
  • Dimer
  • Drug resistance
  • SAXS
  • Virus restriction
  • Catalytic Domain
  • Retroviridae Infections/enzymology
  • Humans
  • Scattering, Small Angle
  • RNA, Viral/chemistry
  • Retroviridae/genetics
  • DNA, Single-Stranded/chemistry
  • Cytidine Deaminase/chemistry
  • Mutation
  • Dimerization
  • Minor Histocompatibility Antigens/chemistry

PubMed: MeSH publication types

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

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