6ZY7

Cryo-EM structure of the entire Human topoisomerase II alpha in State 1

Summary for 6ZY7

• Entry DOI: 10.2210/pdb6zy7/pdb
• EMDB information: 11553
• Descriptor: DNA topoisomerase 2-alpha, DNA (5'-D(*CP*GP*CP*GP*CP*AP*TP*CP*GP*TP*CP*AP*TP*CP*CP*TP*C)-3'), DNA (5'-D(*GP*AP*GP*GP*AP*TP*GP*AP*CP*GP*AP*TP*G)-3'), ... (5 entities in total)
• Functional Keywords: human topoisomerase, etoposide, dna, isomerase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 369858.26

Authors

Vanden Broeck, A.,Lamour, V. (deposition date: 2020-07-30, release date: 2021-05-26, Last modification date: 2024-05-01)

Primary citation

Vanden Broeck, A.,Lotz, C.,Drillien, R.,Haas, L.,Bedez, C.,Lamour, V.
Structural basis for allosteric regulation of Human Topoisomerase II alpha.
Nat Commun, 12:2962-2962, 2021

PubMed Abstract: 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.

PubMed: 34016969
DOI: 10.1038/s41467-021-23136-6

Experimental method

ELECTRON MICROSCOPY (4.64 Å)