Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1.
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Platinum therapeutic agents are widely used in the treatment of several forms of cancer. Various mechanisms for the transport of the drugs have been proposed including passive diffusion across the cellular membrane and active transport via proteins. The copper transport protein Ctr1 is responsible for high affinity copper uptake but has also been implicated in the transport of cisplatin into cells. Human hCtr1 contains two methionine-rich Mets motifs on its extracellular N-terminus that are potential platinum-binding sites: the first one encompasses residues 7-14 with amino acid sequence Met-Gly-Met-Ser-Tyr-Met-Asp-Ser and the second one spans residues 39-46 with sequence Met-Met-Met-Met-Pro-Met-Thr-Phe. In these studies, we use liquid chromatography and mass spectrometry to compare the binding interactions between cisplatin, carboplatin and oxaliplatin with synthetic peptides corresponding to hCtr1 Mets motifs. The interactions of cisplatin and carboplatin with Met-rich motifs that contain three or more methionines result in removal of the carrier ligands of both platinum complexes. In contrast, oxaliplatin retains its cyclohexyldiamine ligand upon platinum coordination to the peptide.
SubjectAmino Acid Motifs
Amino Acid Sequence
Amino Acid Substitution
Cation Transport Proteins
Molecular Sequence Annotation
Molecular Sequence Data
Published Version (Please cite this version)10.1039/b916899k
Publication InfoCrider, Sarah E; Holbrook, Robert J; & Franz, Katherine J (2010). Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1. Metallomics, 2(1). pp. 74-83. 10.1039/b916899k. Retrieved from https://hdl.handle.net/10161/4118.
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Member of the Duke Cancer Institute
Research in the Franz group is involved in elucidating the structural and functional consequences of metal ion coordination in biological systems. We are particularly interested in understanding the coordination chemistry utilized by biology to manage essential yet toxic species like copper and iron. Understanding these principles further guides our development of new chemical tools to manipulate biological metal ion location, speciation, and reactivity for potential therapeutic benefit. We use