Interaction of cisplatin and analogues with a Met-rich protein site |
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Authors: | Chak Ming Sze George N Khairallah Zhiguang Xiao Paul S Donnelly Richard A J O’Hair Anthony G Wedd |
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Institution: | (1) School of Chemistry and the Bio21 Institute, University of Melbourne, Melbourne, VIC, 3010, Australia |
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Abstract: | The chaperone protein CopC from Pseudomonas syringae features high-affinity binding sites (K
D ~ 10−13 M) for both CuI (Met-rich) and CuII (His-rich). When presented with these sites in the apoprotein, electrospray ionisation mass spectrometry confirmed that cis-Pt(NH3)2Cl2 (cisplatin) and the fragments PtIIL]2+ (L is 1,2-diaminoethane, 2,2′-bipyridine) occupied the CuI site specifically in the 1:1 Pt–CopC adducts (purified by cation-exchange chromatography). The cis-Pt(NH3)2 fragment was not present in these adducts (the dominant product for cisplatin was Pt–CopC in which all original ligands were
displaced), while bidentate ligands L were retained in LPt–CopC adducts. In the context of the Met-rich CuI pump Ctr1 as a significant entry point for cisplatin into mammalian cells, the present work confirms the ability of Met-rich
sites in proteins to remove all ligands from cisplatin. It focuses attention on the potential of proteins that are part of
the natural copper transport pathways to sequester the drug. These pathways are worthy of further study at the molecular level.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Cisplatin Copper chaperone proteins Cation exchange Mass spectrometry |
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