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@ARTICLE{Calandrini:201315,
author = {Calandrini, Vania and Arnesano, Fabio and Galliani, Angela
and Nguyen, Trung Hai and Ippoliti, Emiliano and Carloni,
Paolo and Natile, Giovanni},
title = {{P}latination of the copper transporter {ATP}7{A} involved
in anticancer drug resistance},
journal = {Dalton transactions},
volume = {43},
number = {31},
issn = {1477-9234},
address = {London},
publisher = {Soc.},
reportid = {FZJ-2015-03620},
pages = {12085 -},
year = {2014},
abstract = {The clinical efficacy of the widely used anticancer drug
cisplatin is severely limited by the emergence of
resistance. This is related to the drug binding to proteins
such as the copper influx transporter Ctr1, the copper
chaperone Atox1, and the copper pumps ATP7A and ATP7B. While
the binding modes of cisplatin to the first two proteins are
known, the structural determinants of platinated ATP7A/ATP7B
are lacking. Here we investigate the interaction of
cisplatin with the first soluble domain of ATP7A. First, we
establish by ESI-MS and 1H, 13C, and 15N NMR that, in
solution, the adduct is a monomer in which the sulfur atoms
of residues Cys19 and Cys22 are cis-coordinated to the
[Pt(NH3)2]2+ moiety. Then, we carry out hybrid
Car–Parrinello QM/MM simulations and computational
spectroscopy calculations on a model adduct based on the NMR
structure of the apo protein and featuring the
experimentally determined binding mode of the metal ion.
These calculations show quantitative agreement with CD
spectra and 1H, 13C, and 15N NMR chemical shifts, thus
providing a quantitative molecular view of the 3D binding
mode of cisplatin to ATP7A. Importantly, the same comparison
rules out a variety of alternative models with different
coordination modes, that we explored to test the robustness
of the computational approach. Using this combined in
silico–in vitro approach we provide here for the first
time a quantitative 3D atomic view of the platinum binding
to the first soluble domain of ATP7A.},
cin = {INM-9 / IAS-5 / GRS},
ddc = {540},
cid = {I:(DE-Juel1)INM-9-20140121 / I:(DE-Juel1)IAS-5-20120330 /
I:(DE-Juel1)GRS-20100316},
pnm = {899 - ohne Topic (POF2-899)},
pid = {G:(DE-HGF)POF2-899},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000339862400036},
pubmed = {pmid:24983998},
doi = {10.1039/C4DT01339E},
url = {https://juser.fz-juelich.de/record/201315},
}