Exploring metallodrug-protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound.
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.
Casini
Angela
A
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. angela.casini@epfl.ch
Gabbiani
Chiara
C
Michelucci
Elena
E
Pieraccini
Giuseppe
G
Moneti
Gloriano
G
Dyson
Paul J
PJ
Messori
Luigi
L
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
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