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

Lookup NU author(s): Elise Ling, Dr Arnaud Basle, Dr Ian Cowell, Professor Bert van den Berg, Professor Caroline AustinORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 Ȧ 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 provides fundamental insights into the tertiary structure of the human TOP2B ATPase domain and a potential regulatory mechanism for ATP hydrolysis.


Publication metadata

Author(s): Ling EM, Baslé A, Cowell IG, van den Berg B, Blower TR, Austin CA

Publication type: Article

Publication status: Published

Journal: Structure

Year: 2022

Pages: epub ahead of pub

Online publication date: 03/06/2022

Acceptance date: 10/05/2022

Date deposited: 18/07/2022

ISSN (electronic): 1878-4186

Publisher: Elsevier

URL: https://doi.org/10.1016/j.str.2022.05.009

DOI: 10.1016/j.str.2022.05.009


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Funding

Funder referenceFunder name
BB/M011186/1
BSRC

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