Catalytic mechanism of ATP hydrolysis in the ATPase domain of human DNA topoisomerase IIα
ID Ogrizek, Mitja (Author), ID Janežič, Matej (Author), ID Valjavec, Katja (Author), ID Perdih, Andrej (Author)

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Human DNA topoisomerase IIα is a biological nanomachine that regulates the topological changes of the DNA molecule and is considered a prime target for anticancer drugs. Despite intensive research, many atomic details about its mechanism of action remain unknown. We investigated the ATPase domain, a segment of the human DNA topoisomerase IIα, using all-atom molecular simulations, multiscale quantum mechanics/molecular mechanics (QM/MM) calculations, and a point mutation study. The results suggested that the binding of ATP affects the overall dynamics of the ATPase dimer. Reaction modeling revealed that ATP hydrolysis favors the dissociative substrate-assisted reaction mechanism with the catalytic Glu87 serving to properly position and polarize the lytic water molecule. The point mutation study complemented our computational results, demonstrating that Lys378, part of the important QTK loop, acts as a stabilizing residue. The work aims to pave the way to a deeper understanding of these important molecular motors and to advance the development of new therapeutics.

Work type:Article
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Publication status:Published
Publication version:Version of Record
Number of pages:Str. 3896–3909
Numbering:Vol. 62, iss. 16
PID:20.500.12556/RUL-140838 This link opens in a new window
ISSN on article:1549-9596
DOI:10.1021/acs.jcim.2c00303 This link opens in a new window
COBISS.SI-ID:120437251 This link opens in a new window
Publication date in RUL:19.09.2022
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Record is a part of a journal

Title:Journal of chemical information and modeling
Shortened title:J. chem. inf. mod.
Publisher:American Chemical Society
COBISS.SI-ID:26533125 This link opens in a new window


License:CC BY 4.0, Creative Commons Attribution 4.0 International
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

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Keywords:biokemija, DNK, topoizomeraze, simulacije


Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P1-0012
Name:Molekulske simulacije, bioinformatika in načrtovanje zdravilnih učinkovin

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