Modeling the Structure of Human tRNA-Guanine Transglycosylase in Complex with 7-Methylguanine and Revealing the Factors that Determine the Enzyme Interaction with Inhibitors

tRNA-guanine transglycosylase, an enzyme catalyzing replacement of guanine with queuine in human tRNA and participating in the translation mechanism, is involved in the development of cancer. However, information on the small-molecule inhibitors that can suppress activity of this enzyme is very limi...

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Bibliographic Details
Published in:Biochemistry (Moscow) 2022-05, Vol.87 (5), p.443-449
Main Authors: Pushkarev, Sergey V., Vinnik, Valeriia A., Shapovalova, Irina V., Švedas, Vytas K., Nilov, Dmitry K.
Format: Article
Language:English
Subjects:
Adenosine diphosphate
Amino acids
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Complex formation
DNA repair
Enzymes
Guanine
Hydrogen
Hydrogen bonding
Hydrogen bonds
Hydrophobicity
Inhibitors
Life Sciences
Methylguanine
Microbiology
Molecular dynamics
Poly(ADP-ribose)
Poly(ADP-ribose) polymerase
Residues
Ribose
Transfer RNA
tRNA
tRNA-guanine transglycosylase
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Summary:tRNA-guanine transglycosylase, an enzyme catalyzing replacement of guanine with queuine in human tRNA and participating in the translation mechanism, is involved in the development of cancer. However, information on the small-molecule inhibitors that can suppress activity of this enzyme is very limited. Molecular dynamics simulations were used to determine the amino acid residues that provide efficient binding of inhibitors in the active site of tRNA-guanine transglycosylase. It was demonstrated using 7-methylguanine molecule as a probe that the ability of the inhibitor to adopt a charged state in the environment of hydrogen bond acceptors Asp105 and Asp159 plays a key role in complex formation. Formation of the hydrogen bonds and hydrophobic contacts with Gln202, Gly229, Phe109, and Met259 residues are also important. It has been predicted that introduction of the substituents would have a different effect on the ability to inhibit tRNA-guanine transglycosylase, as well as the DNA repair protein poly(ADP-ribose) polymerase 1, which can contribute to the development of more efficient and selective compounds.
ISSN:0006-2979
1608-3040
DOI:10.1134/S0006297922050054