Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine

  • Int J Mol Sci. 2020 Mar 20;21(6):2159. doi: 10.3390/ijms21062159.
Dmitry Nilov  1 ,  Natalya Maluchenko  2 ,  Tatyana Kurgina  3  4 ,  Sergey Pushkarev  5 ,  Alexandra Lys  2 ,  Mikhail Kutuzov  3 ,  Nadezhda Gerasimova  2 ,  Alexey Feofanov  2  6 ,  Vytas Švedas  1  5 ,  Olga Lavrik  3  4 ,  Vasily M Studitsky  2  7
Affiliations
  • 1. Lomonosov Moscow State University, Belozersky Institute of Physicochemical Biology, Lenin Hills 1, bldg. 40, 119991 Moscow, Russia.
  • 2. Lomonosov Moscow State University, Biology Faculty, Lenin Hills 1, bldg. 12, 119992 Moscow, Russia.
  • 3. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev avenue 8, 630090 Novosibirsk, Russia.
  • 4. Novosibirsk State University, Pirogov str. 2, 630090 Novosibirsk, Russia.
  • 5. Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Lenin Hills 1, bldg. 73, 119991 Moscow, Russia.
  • 6. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya str. 16/10, 117997 Moscow, Russia.
  • 7. Fox Chase Cancer Center, Cottman Avenue 333, Philadelphia, PA 19111-2497, USA.
PMID: 32245127 DOI: 10.3390/ijms21062159
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.

Keywords
7-methylguanine; docking; fluorescence anisotropy; inhibitor; molecular dynamics; nucleosome; poly(ADP-ribose) polymerase 1; spFRET microscopy; trapping.
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