Trung Hai Nguyen; Arnesano, Fabio; Scintilla, Simone; Rossetti, Giulia; Ippoliti, Emiliano; Carloni, Paolo; Natile, Giovanni
Structural Determinants of Cisplatin and Transplatin Binding to the Met-Rich Motif of Ctr1: A Computational Spectroscopy Approach
JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 8:2912-2920, AUG 2012

The cellular uptake of cisplatin and of other platinum-based drugs is mediated by the high-affinity, copper transporter Ctr1. The eight residue long peptide called Mets7 (MTGMKGMS) mimics one of extracellular methionine (Met)-rich motifs of Ctrl. It is an excellent model for investigating the interaction of platinum drugs with Ctrl under in vitro and in vivo conditions. Some of us have shown that (i) Cisplatin loses all of its ligands upon reaction with Mets7 and the metal ion binds to the three Met residues and completes its coordination shell with a fourth ligand that can be a chloride or a water/hydroxyl oxygen. (ii) Transplatin loses only the chlorido ligands, which are replaced by Met residues. Here, we provide information on the structural determinants of cisplatin/Mets7 and transplatin/Mets7 adducts by computational methods. The predictions are validated against EXAFS, NMR, and CD spectra. While EXAFS gives information restricted to the metal coordination shell, NMR provides information extended to residue atoms around the coordination shell, and finally, CD provides information about the overall conformation of the peptide. This allows us to elucidate the different reaction modes of cisplatin and transplatin toward the peptide, as well as to propose the platinated peptides [PtX](+)-(M*TGM*KGM*S) (X = Cl-, OH-) and trans[Pt(NH3)(2)](2+)-(M*TGM*KGMS) as the most relevant species occurring in water solution.

DOI:10.1021/ct300167m

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