A comprehensive structural analysis of the ATPase domain of Human DNA topoisomerase II Beta bound to AMPPNP, ADP and the bisdioxopiperazine, ICRF193

Ling, E.M.; Baslé, A.; Cowell, I.G.; Van Den Berg, B.; Blower, T.R.; Austin, C.A.

doi:10.1016/j.str.2022.05.009

A comprehensive structural analysis of the ATPase domain of Human DNA topoisomerase II Beta bound to AMPPNP, ADP and the bisdioxopiperazine, ICRF193

Ling, E.M.; Baslé, A.; Cowell, I.G.; Van Den Berg, B.; Blower, T.R.; Austin, C.A.

Authors

E.M. Ling

A. Baslé

I.G. Cowell

B. Van Den Berg

Professor Tim Blower timothy.blower@durham.ac.uk
Professor

C.A. Austin

Abstract

Human topoisomerase II beta (TOP2B) modulates DNA topology using energy from ATP hydrolysis. To investigate the conformational changes that occur during ATP hydrolysis, we determined the X-ray crystallographic structures of the human TOP2B ATPase domain bound to AMPPNP or ADP at 1.9 Å and 2.6 Å resolution, respectively. The GHKL domains of both structures are similar, whereas the QTK loop within the transducer domain can move for product release. As TOP2B is the clinical target of bisdioxopiperazines, we also determined the structure of a TOP2B:ADP:ICRF193 complex to 2.3 Å resolution and identified key drug-binding residues. Biochemical characterization revealed the N-terminal strap reduces the rate of ATP hydrolysis. Mutagenesis demonstrated residue E103 as essential for ATP hydrolysis in TOP2B. Our data provide fundamental insights into the tertiary structure of the human TOP2B ATPase domain and a potential regulatory mechanism for ATP hydrolysis.

Citation

Ling, E., Baslé, A., Cowell, I., Van Den Berg, B., Blower, T., & Austin, C. (2022). A comprehensive structural analysis of the ATPase domain of Human DNA topoisomerase II Beta bound to AMPPNP, ADP and the bisdioxopiperazine, ICRF193. Structure, 30(8), P1129-1145.e3. https://doi.org/10.1016/j.str.2022.05.009

Journal Article Type	Article
Acceptance Date	May 10, 2022
Online Publication Date	Jun 3, 2022
Publication Date	Aug 4, 2022
Deposit Date	May 5, 2022
Publicly Available Date	Jan 31, 2023
Journal	Structure
Print ISSN	0969-2126
Electronic ISSN	1878-4186
Publisher	Elsevier
Peer Reviewed	Peer Reviewed
Volume	30
Issue	8
Pages	P1129-1145.e3
DOI	https://doi.org/10.1016/j.str.2022.05.009

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© 2022 The Author(s). Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).