Molecular mechanisms of PARP-1 inhibitor 7-methylguanine

Dmitry Nilov, Natalya Maluchenko, Tatyana Kurgina, Sergey Pushkarev, Alexandra Lys, Mikhail Kutuzov, Nadezhda Gerasimova, Alexey Feofanov, Vytas Švedas, Olga Lavrik, Vasily M. Studitsky

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

7-Methylguanine (7-MG), a natural compound that inhibits DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1), can be considered as a potential anticancer drug candidate. Here we describe a study of 7-MG inhibition mechanism using molecular dynamics, fluorescence anisotropy and single-particle Förster resonance energy transfer (spFRET) microscopy approaches to elucidate intermolecular interactions between 7-MG, PARP-1 and nucleosomal DNA. It is shown that 7-MG competes with substrate NAD+ and its binding in the PARP-1 active site is mediated by hydrogen bonds and nonpolar interactions with the Gly863, Ala898, Ser904, and Tyr907 residues. 7-MG promotes formation of the PARP-1–nucleosome complexes and suppresses DNA-dependent PARP-1 automodification. This results in nonproductive trapping of PARP-1 on nucleosomes and likely prevents the removal of genotoxic DNA lesions.

Original languageEnglish
Article number2159
Number of pages11
JournalInternational Journal of Molecular Sciences
Volume21
Issue number6
DOIs
Publication statusPublished - Mar 2020

Keywords

  • 7-methylguanine
  • Docking
  • Fluorescence anisotropy
  • Inhibitor
  • Molecular dynamics
  • Nucleosome
  • Poly(ADP-ribose) polymerase 1
  • SpFRET microscopy
  • Trapping
  • poly(ADP-ribose) polymerase 1
  • POLY(ADP-RIBOSE) POLYMERASE
  • DOCKING
  • trapping
  • molecular dynamics
  • ACCURACY
  • docking
  • THERAPY
  • inhibitor
  • spFRET microscopy
  • fluorescence anisotropy
  • nucleosome
  • BINDING

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