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Nilov D, Maluchenko N, Kurgina T, Pushkarev S, Lys A, Kutuzov M, Gerasimova N, Feofanov A, Svedas V, Lavrik O, Studitsky VM
Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine
Int J Mol Sci (2020) In process.
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 Forster 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.
Publication Date: 2020-03-20.
PMCID: PMC7139824
Last updated on Saturday, August 22, 2020