Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/ijms21062159
Keywords
7-methylguanine; poly(ADP-ribose) polymerase 1; inhibitor; nucleosome; trapping; docking; molecular dynamics; fluorescence anisotropy; spFRET microscopy
Funding
- Russian Science Foundation [19-74-10072]
- Russian Foundation for Basic Research [17-00-00163, 17-00-00132, 17-00-00097]
- Russian Science Foundation [19-74-10072] Funding Source: Russian Science Foundation
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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.
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