title: Exploring metallodrug-protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound.
abstract: Electrospray ionisation mass spectrometry was used to analyse the reactions of metal compounds with mixtures of selected proteins. Three representative medicinally relevant compounds, cisplatin, transplatin and the organometallic ruthenium compound RAPTA-C, were reacted with a pool of three proteins, ubiquitin, cytochrome c and superoxide dismutase, and the reaction products were analysed using high-resolution mass spectrometry. Highly informative electrospray ionisation mass spectra were acquired following careful optimisation of the experimental conditions. The formation of metal-protein adducts was clearly observed for the three proteins. In addition, valuable information was obtained on the nature of the protein-bound metallofragments, on their distribution among the three different proteins and on the binding kinetics. The platinum compounds were less reactive and considerably less selective in protein binding than RAPTA-C, which showed a high affinity towards ubiquitin and cytochrome c, but not superoxide dismutase. In addition, competition studies between cisplatin and RAPTA-C showed that the two metallodrugs have affinities for the same amino acid residues on protein binding.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. angela.casini@epfl.ch
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabbiani
authors.forename: Elena
authors.initials: E
authors.lastname: Michelucci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pieraccini
authors.forename: Gloriano
authors.initials: G
authors.lastname: Moneti
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism*; D000081007:Cymenes; D045304:Cytochromes c / Q000378:metabolism; D006736:Horses; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000081007:Cymenes; D009942:Organometallic Compounds; D011506:Proteins; D025801:Ubiquitin; C530402:dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II); C034697:transplatin; D045304:Cytochromes c; D013482:Superoxide Dismutase; D002945:Cisplatin