Mechanism of PARP1 elongation reaction revealed by molecular modeling

Авторы: Pushkarev S.V., Kirilin E.M., Švedas V.K., Nilov D.K.
Журнал: Biochemistry (Moscow)
Том: 89
Номер: 7
Год издания: 2024
Издательство: Pleiades Publishing, Ltd
Местоположение издательства: Road Town, United Kingdom
Первая страница: 1202
Последняя страница: 1210
DOI: 10.1134/S0006297924070046
Аннотация: Poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in the DNA damage repair and transcriptionalregulation, and is targeted by a number of clinical inhibitors. Despite this, catalytic mechanism of PARP1 remains largely underexplored because of the complex substrate/product structure. Using molecular modeling and metadynamics simulations we have described in detail elongation of poly(ADP-ribose) chain in the PARP1 active site. It was shown that elongation reaction proceeds via the SN1-like mechanism involving formation of the intermediate furanosyl oxocarbenium ion. Intriguingly, nucleophilic 2′A-OH group of the acceptor substrate can be activated by the general base Glu988 not directly but through the proton relay system including the adjacent 3′A-OH group.
Добавил в систему: Нилов Дмитрий Константинович

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