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

Pushkarev, S.V.; Vinnik, V.A.; Shapovalova, I.V.; Švedas, V.K.; Nilov, D.K.

Авторы: Pushkarev Sergey V., Vinnik Valeriia A., Shapovalova Irina V., Švedas Vytas K., Nilov Dmitry K.
Журнал: Biochemistry (Moscow)
Том: 87
Номер: 5
Год издания: 2022
Издательство: Pleiades Publishing, Ltd
Местоположение издательства: Road Town, United Kingdom
Первая страница: 443
Последняя страница: 449
Оригинальные версии: Моделирование структуры комплекса тРНК-гуанинтрансгликозилазы человека с 7-метилгуанином и выявление факторов, определяющих взаимодействие фермента с ингибиторами
DOI: 10.1134/s0006297922050054
Аннотация: 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. Ithas 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.
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Modeling the Structure of Human tRNA-Guanine Transglycosylase in Complex with 7-Methylguanine and Revealing the Factors that Determine the Enzyme Interaction with Inhibitorsстатья

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