Structural biology of cisplatin complexes with cellular targets: the adduct with human copper chaperone atox1 in aqueous solution.

Vania Calandrini, Trung Hai Nguyen, Fabio Arnesano, Angela Galliani, Emiliano Ippoliti, Paolo Carloni, Giovanni Natile

Journal: Chemistry (Weinheim an der Bergstrasse, Germany) 2015;20(37):11719-25

PMID: 25111319

Abstract

Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DNA may involve the copper chaperone Atox1 protein. Although the mode of binding is established by NMR spectroscopy measurements in solution-the Pt atom binds to Cys12 and Cys15 while retaining the two ammine groups-the structural determinants of the adduct are not known. Here a structural model by hybrid Car-Parrinello density functional theory-based QM/MM simulations is provided. The platinated site minimally modifies the fold of the protein. The calculated NMR and CD spectral properties are fully consistent with the experimental data. Our in silico/in vitro approach provides, together with previous studies, an unprecedented view into the structural biology of cisplatin-protein adducts.

Address: Computational Biophysics, German Research School for Simulation Sciences, 52425 Jülich (Germany); Computational Biomedicine, Institute for Advanced Simulation IAS-5, Forschungszentrum Jülich, 52425 (Germany); Computational Biomedicine, Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425 Jülich (Germany).

DOI: 10.1002/chem.201402834

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https://doi.org/10.1002/chem.201402834

MeSH Terms: Antineoplastic Agents, Cisplatin, Copper, Copper Transport Proteins, Humans, Metallochaperones, Models, Molecular, Molecular Chaperones, Protein Binding