Topoisomerase I (TOP1) dynamics: conformational transition from open to closed states

Diane T. Takahashi (), Danièle Gadelle, Keli Agama, Evgeny Kiselev, Hongliang Zhang, Emilie Yab, Stephanie Petrella, Patrick Forterre, Yves Pommier () and Claudine Mayer
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Diane T. Takahashi: Université Paris-Saclay
Danièle Gadelle: Université Paris-Saclay
Keli Agama: Center for Cancer Research, NCI, NIH
Evgeny Kiselev: Center for Cancer Research, NCI, NIH
Hongliang Zhang: Center for Cancer Research, NCI, NIH
Emilie Yab: Université de Paris, CNRS UMR 3528, Unité de Microbiologie Structurale
Stephanie Petrella: Université de Paris, CNRS UMR 3528, Unité de Microbiologie Structurale
Patrick Forterre: Université Paris-Saclay
Yves Pommier: Center for Cancer Research, NCI, NIH
Claudine Mayer: Université de Paris, CNRS UMR 3528, Unité de Microbiologie Structurale

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Eukaryotic topoisomerases I (TOP1) are ubiquitous enzymes removing DNA torsional stress. However, there is little data concerning the three-dimensional structure of TOP1 in the absence of DNA, nor how the DNA molecule can enter/exit its closed conformation. Here, we solved the structure of thermostable archaeal Caldiarchaeum subterraneum CsTOP1 in an apo-form. The enzyme displays an open conformation resulting from one substantial rotation between the capping (CAP) and the catalytic (CAT) modules. The junction between these two modules is a five-residue loop, the hinge, whose flexibility permits the opening/closing of the enzyme and the entry of DNA. We identified a highly conserved tyrosine near the hinge as mediating the transition from the open to closed conformation upon DNA binding. Directed mutagenesis confirmed the importance of the hinge flexibility, and linked the enzyme dynamics with sensitivity to camptothecin, a TOP1 inhibitor targeting the TOP1 enzyme catalytic site in the closed conformation.

Date: 2022
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DOI: 10.1038/s41467-021-27686-7

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