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

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

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.

• Jezik: Angleški jezik
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2022
• Št. strani: Str. 3896–3909
• Številčenje: Vol. 62, iss. 16
• PID: 20.500.12556/RUL-140838
• UDK: 577
• ISSN pri članku: 1549-9596
• DOI: 10.1021/acs.jcim.2c00303
• COBISS.SI-ID: 120437251
• Datum objave v RUL: 19.09.2022

Gradivo je del revije

• Naslov: Journal of chemical information and modeling
• Skrajšan naslov: J. chem. inf. mod.
• Založnik: American Chemical Society
• ISSN: 1549-9596
• COBISS.SI-ID: 26533125

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: biokemija, DNK, topoizomeraze, simulacije

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0012
• Naslov: Molekulske simulacije, bioinformatika in načrtovanje zdravilnih učinkovin