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Lookup NU author(s): Elise Ling, Dr Arnaud Basle, Dr Ian CowellORCiD, Professor Bert van den Berg, Professor Caroline AustinORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
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
Volume: 30
Issue: 8
Pages: 1129-1145.e3
Print publication date: 04/08/2022
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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