Characterization of platinum anticancer drug protein-binding sites using a top-down mass spectrometric approach.
A proof-of-principle study on the application of a top-down electrospray ionization Fourier transform ion cyclotron resonance mass spectrometric approach for characterization of the primary binding sites of the platinum anticancer agents cisplatin, transplatin, and oxaliplatin on ubiquitin is presented. Through employment of different fragmentation techniques, the binding sites of cisplatin and oxaliplatin were found at N-terminal methionine-containing ubiquitin fragments, while transplatin was observed to be attached to 19Pro-Ser-Asp-Thr-Ile-Glu24. The binding to proteins is of particular relevance for the mode of action of metallodrugs with regard to (de)activation, transport, excretion, etc. To the best of our knowledge, this is the first top-down mass spectrometric study on the protein binding site characterization of transition-metal anticancer agents and demonstrates the potential of the applied technique for investigating metal drug-protein interactions.
Hartinger
Christian G
CG
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland. christian.hartinger@univie.ac.at
Tsybin
Yury O
YO
Fuchser
Jens
J
Dyson
Paul J
PJ
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D013058:Mass Spectrometry / Q000379:methods; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D000077150:Oxaliplatin; D017434:Protein Structure, Tertiary; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D013329:Structure-Activity Relationship; D025801:Ubiquitin / Q000737:chemistry* / Q000187:drug effects
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D025801:Ubiquitin; D000077150:Oxaliplatin; C034697:transplatin; D002945:Cisplatin