title: Reactivity of platinum-based antitumor drugs towards a Met- and His-rich 20mer peptide corresponding to the N-terminal domain of human copper transporter 1.
abstract: Cellular uptake of platinum-based antitumor drugs is a critical step in the mechanism of the drug action and associated resistance, and deeper understanding of this step may inspire development of novel methods for new drugs with reduced resistance. Human copper transporter 1 (hCtr1), a copper influx protein, was recently found to facilitate the cellular entry of several platinum drugs. In the work reported here, we constructed a Met- and His-rich 20mer peptide (hCtr1-N20) corresponding to the N-terminal domain of hCtr1, which is the essential domain of hCtr1 for transporting platinum drugs. The interactions of the peptide with cisplatin and its analogues, including transplatin, carboplatin, oxaliplatin, and [Pt(L: -Met)Cl(2)], were explored at the molecular level. Electrospray ionization (ESI) mass spectrometry (MS) data revealed that all of the platinum(II) complexes used in present study can bind to hCtr1-N20 in 1:1 and 2:1 stoichiometry. Four Met residues should be involved in binding to cis-platinum complexes on the basis of the tandem MS spectrometry and previously reported data. Time-dependent 2D [(1)H,(15)N] heteronuclear single quantum coherence NMR spectra indicate the reaction of cisplatin with hCtr1-N20 is a stepwise process. The intermediate, however, is transient, which is consistent with the ESI-MS results. Time-dependent ESI-MS data revealed that the geometry and the properties of both the leaving and the nonleaving groups of platinum(II) complexes play essential roles in controlling the reactivity and formation of the final products with hCtr1-N20.
authors: State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, 210093 Nanjing, People's Republic of China.
authors: Zhengyi
authors: Z
authors: Wu
authors: Qin
authors: Q
authors: Liu
authors: Xiao
authors: X
authors: Liang
authors: Xiaoliang
authors: X
authors: Yang
authors: Ningyan
authors: N
authors: Wang
authors: Xinghao
authors: X
authors: Wang
authors: Hongzhe
authors: H
authors: Sun
authors: Yi
authors: Y
authors: Lu
authors: Zijian
authors: Z
authors: Guo
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D002942:Circular Dichroism; D002945:Cisplatin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D000079923:Copper Transporter 1; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008715:Methionine / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000235:genetics; D010984:Platinum / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D010455:Peptides; D010984:Platinum; D006639:Histidine; D003300:Copper; D008715:Methionine; D002945:Cisplatin