Premium
Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution
Author(s) -
Calandrini Vania,
Nguyen Trung Hai,
Arnesano Fabio,
Galliani Angela,
Ippoliti Emiliano,
Carloni Paolo,
Natile Giovanni
Publication year - 2014
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201402834
Subject(s) - adduct , chaperone (clinical) , in silico , cisplatin , chemistry , nuclear magnetic resonance spectroscopy , stereochemistry , aqueous solution , copper , combinatorial chemistry , biochemistry , biophysics , biology , organic chemistry , gene , genetics , medicine , pathology , chemotherapy
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.