title: Molecular Simulations Highlight the Role of Metals in Catalysis and Inhibition of Type II Topoisomerase.
abstract: Type II topoisomerase (topoII) is a metalloenzyme targeted by clinical antibiotics and anticancer agents. Here, we integrate existing structural data with molecular simulation and propose a model for the yet uncharacterized structure of the reactant state of topoII. This model describes a canonical two-metal-ion mechanism and suggests how the metals could rearrange at the catalytic pocket during enzymatic turnover, explaining also experimental evidence for topoII inhibition. These results call for further experimental validation.
authors.affiliation: Department of Drug Discovery and Development, Italian Institute of Technology, via Morego 30, 16163 Genova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Palermo
authors.affiliation: Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne - EPFL, Lausanne, CH-1015, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Stenta
authors.affiliation: Department of Drug Discovery and Development, Italian Institute of Technology, via Morego 30, 16163 Genova, Italy.|Department of Pharmaceutical Sciences, University of Bologna, via Belmeloro 6, I-40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne - EPFL, Lausanne, CH-1015, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Dal Peraro
authors.affiliation: Department of Drug Discovery and Development, Italian Institute of Technology, via Morego 30, 16163 Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Vivo