Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine
D. K. Nilov, Natalya Maluchenko, Tatyana A. Kurgina, Sergey V. Pushkarev, Alexandra Lys, Mikhail M. Kutuzov, Н. С. Герасимова, Alexey V. Feofanov, Vytas K. Švedas, Olga I. Lavrik, Vasily M. Studitsky
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.