title: Structural Determinants of Cisplatin and Transplatin Binding to the Met-Rich Motif of Ctr1: A Computational Spectroscopy Approach.
abstract: 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 Ctr1. It is an excellent model for investigating the interaction of platinum drugs with Ctr1 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.
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences , D-52425 Jülich, Germany, and Institute for Advanced Simulation, Forschungszentrum Jülich , D-52425 Jülich, Germany.
authors.forename: Trung Hai
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Department Farmaco-Chimico, University of Bari "A. Moro" , via Edoardo Orabona 4, 70125 Bari, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Arnesano
authors.affiliation: Department Farmaco-Chimico, University of Bari "A. Moro" , via Edoardo Orabona 4, 70125 Bari, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Scintilla
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences , D-52425 Jülich, Germany, and Institute for Advanced Simulation, Forschungszentrum Jülich , D-52425 Jülich, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences , D-52425 Jülich, Germany, and Institute for Advanced Simulation, Forschungszentrum Jülich , D-52425 Jülich, Germany.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Ippoliti
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences , D-52425 Jülich, Germany, and Institute for Advanced Simulation, Forschungszentrum Jülich , D-52425 Jülich, Germany.|Statistical and Biological Physics Sector, Scuola Internazionale Superiore di Studi Avanzati (SISSA) , Via Bonomea 265, I-34136 Trieste, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.affiliation: Department Farmaco-Chimico, University of Bari "A. Moro" , via Edoardo Orabona 4, 70125 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile