Determinants of Oligonucleotide Selectivity of APOBEC3B

Jeffrey R. Wagner, Özlem Demir, Michael A. Carpenter, Hideki Aihara, Daniel A Harki, Reuben Harris, Rommie E. Amaro

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

APOBEC3B (A3B) is a prominent source of mutation in many cancers. To date, it has been difficult to capture the native protein-DNA interactions that confer A3B's substrate specificity by crystallography due to the highly dynamic nature of wild-type A3B active site. We use computational tools to restore a recent crystal structure of a DNA-bound A3B C-terminal domain mutant construct to its wild type sequence, and run molecular dynamics simulations to study its substrate recognition mechanisms. Analysis of these simulations reveal dynamics of the native A3Bctd-oligonucleotide interactions, including the experimentally inaccessible loop 1-oligonucleotide interactions. A second series of simulations in which the target cytosine nucleotide was computationally mutated from a deoxyribose to a ribose show a change in sugar ring pucker, leading to a rearrangement of the binding site and revealing a potential intermediate in the binding pathway. Finally, apo simulations of A3B, starting from the DNA-bound open state, experience a rapid and consistent closure of the binding site, reaching conformations incompatible with substrate binding. This study reveals a more realistic and dynamic view of the wild type A3B binding site and provides novel insights for structure-guided design efforts for A3B.

Original languageEnglish (US)
Pages (from-to)2264-2273
Number of pages10
JournalJournal of Chemical Information and Modeling
Volume59
Issue number5
DOIs
StatePublished - May 28 2019

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Oligonucleotides
Binding sites
DNA
Binding Sites
determinants
simulation
Cytosine Nucleotides
Substrates
Deoxyribose
Ribose
Crystallography
interaction
Computer simulation
Nucleotides
Sugars
Conformations
Molecular dynamics
Crystal structure
Proteins
cancer

PubMed: MeSH publication types

  • Journal Article

Cite this

Determinants of Oligonucleotide Selectivity of APOBEC3B. / Wagner, Jeffrey R.; Demir, Özlem; Carpenter, Michael A.; Aihara, Hideki; Harki, Daniel A; Harris, Reuben; Amaro, Rommie E.

In: Journal of Chemical Information and Modeling, Vol. 59, No. 5, 28.05.2019, p. 2264-2273.

Research output: Contribution to journalArticle

Wagner, Jeffrey R. ; Demir, Özlem ; Carpenter, Michael A. ; Aihara, Hideki ; Harki, Daniel A ; Harris, Reuben ; Amaro, Rommie E. / Determinants of Oligonucleotide Selectivity of APOBEC3B. In: Journal of Chemical Information and Modeling. 2019 ; Vol. 59, No. 5. pp. 2264-2273.
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