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Structure paper

TitleStructural basis for allosteric regulation of Human Topoisomerase IIα.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 2962, Year 2021
Publish dateMay 20, 2021
AuthorsArnaud Vanden Broeck / Christophe Lotz / Robert Drillien / Léa Haas / Claire Bedez / Valérie Lamour /
PubMed AbstractThe human type IIA topoisomerases (Top2) are essential enzymes that regulate DNA topology and chromosome organization. The Topo IIα isoform is a prime target for antineoplastic compounds used in ...The human type IIA topoisomerases (Top2) are essential enzymes that regulate DNA topology and chromosome organization. The Topo IIα isoform is a prime target for antineoplastic compounds used in cancer therapy that form ternary cleavage complexes with the DNA. Despite extensive studies, structural information on this large dimeric assembly is limited to the catalytic domains, hindering the exploration of allosteric mechanism governing the enzyme activities and the contribution of its non-conserved C-terminal domain (CTD). Herein we present cryo-EM structures of the entire human Topo IIα nucleoprotein complex in different conformations solved at subnanometer resolutions (3.6-7.4 Å). Our data unveils the molecular determinants that fine tune the allosteric connections between the ATPase domain and the DNA binding/cleavage domain. Strikingly, the reconstruction of the DNA-binding/cleavage domain uncovers a linker leading to the CTD, which plays a critical role in modulating the enzyme's activities and opens perspective for the analysis of post-translational modifications.
External linksNat Commun / PubMed:34016969 / PubMed Central
MethodsEM (single particle)
Resolution3.6 - 7.6 Å
Structure data

EMDB-11550, PDB-6zy5:
Cryo-EM structure of the Human topoisomerase II alpha DNA-binding/cleavage domain in State 1
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-11551, PDB-6zy6:
Cryo-EM structure of the Human topoisomerase II alpha DNA-binding/cleavage domain in State 2
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-11552:
Entire Human Top2a - Interface between ATPase and DNA-binding/cleavage domains
Method: EM (single particle) / Resolution: 7.6 Å

EMDB-11553, PDB-6zy7:
Cryo-EM structure of the entire Human topoisomerase II alpha in State 1
Method: EM (single particle) / Resolution: 4.64 Å

EMDB-11554, PDB-6zy8:
Cryo-EM structure of the entire Human topoisomerase II alpha in State 2
Method: EM (single particle) / Resolution: 7.4 Å

Chemicals

ChemComp-EVP:
(5S,5aR,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol / medication, chemotherapy*YM

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

Source
  • homo sapiens (human)
KeywordsISOMERASE / Human Topoisomerase / Etoposide / DNA

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