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Title

Analysis of Etoposide Binding to Subdomains of Human DNA Topoisomerase IIα in the Absence of DNA

Authors
Kajava, Andrey V.
Frei, Christian
Published in Biochemistry. 2001, vol. 40, no. 6, p. 1624-1634
Abstract Epipodophyllotoxins are effective anti-tumor drugs that inhibit eukaryotic DNA topoisomerase II by trapping the enzyme in a covalent complex with DNA. We show that both the recombinant N-terminal ATPase domain and the B‘A‘ core domain of human topoisomerase IIα (htopoIIα) bind radiolabeled etoposide specifically, even in the absence of DNA. The addition of ATP impairs etoposide binding to the holoenzyme and the N-terminal domain, but not to the core domain. To see if this interference resembles that between novobiocin and ATP in the bacterial GyrB subunit, we modeled the structure of the N-terminal domain of htopoIIα and performed molecular docking analysis with etoposide. Mutagenesis of critical amino acids, predicted to stabilize the drug within the N-terminal domain, reveals a less efficient binding of etoposide to the mutated proteins as monitored by direct drug binding assays, although the binding of ATP is not affected.
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Other version: https://pubs.acs.org/doi/10.1021/bi0019141
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LEROY, Didier et al. Analysis of Etoposide Binding to Subdomains of Human DNA Topoisomerase IIα in the Absence of DNA. In: Biochemistry, 2001, vol. 40, n° 6, p. 1624-1634. doi: 10.1021/bi0019141 https://archive-ouverte.unige.ch/unige:123125

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Deposited on : 2019-09-13

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