Catalytic mechanism of ATP hydrolysis in the ATPase domain of human DNA topoisomerase IIα

Ogrizek, Mitja (author), Janežič, Matej (author), Valjavec, Katja (author), Perdih, Andrej (author)

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.

• Language: English
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: Str. 3896–3909
• Numbering: Vol. 62, iss. 16
• PID: 20.500.12556/RUL-140838
• UDC: 577
• ISSN on article: 1549-9596
• DOI: 10.1021/acs.jcim.2c00303
• COBISS.SI-ID: 120437251
• Publication date in RUL: 19.09.2022

Record is a part of a journal

• Title: Journal of chemical information and modeling
• Shortened title: J. chem. inf. mod.
• Publisher: American Chemical Society
• ISSN: 1549-9596
• COBISS.SI-ID: 26533125

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• 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.

Secondary language

• Language: Slovenian
• Keywords: biokemija, DNK, topoizomeraze, simulacije

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0012
• Name: Molekulske simulacije, bioinformatika in načrtovanje zdravilnih učinkovin