A comprehensive structural analysis of the ATPase domain of human DNA topoisomerase II beta bound to AMPPNP, ADP, and the bisdioxopiperazine, ICRF193.

Autor:	Ling EM; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Baslé A; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Cowell IG; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., van den Berg B; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Blower TR; Department of Biosciences, Durham University, South Road, Durham DH1 3LE, UK. Electronic address: timothy.blower@durham.ac.uk., Austin CA; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: caroline.austin@ncl.ac.uk.
Jazyk:	angličtina
Zdroj:	Structure (London, England : 1993) [Structure] 2022 Aug 04; Vol. 30 (8), pp. 1129-1145.e3. Date of Electronic Publication: 2022 Jun 03.
DOI:	10.1016/j.str.2022.05.009
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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