title: Interactions of carboplatin and oxaliplatin with proteins: Insights from X-ray structures and mass spectrometry studies of their ribonuclease A adducts.
abstract: Oxaliplatin and carboplatin are two platinum(II) drugs in widespread clinical use for the treatment of various types of cancers; yet, structural information on their interactions with proteins is scarce. Here, the X-ray structures of the adducts formed upon reaction of carboplatin and oxaliplatin with bovine pancreatic ribonuclease (RNase A) are reported and compared with results obtained for the structure of the RNase A-cisplatin adduct derived from isomorphous crystals, under the same experimental conditions. Additional details on the binding mode of these metallodrugs toward RNase A are provided by electrospray ionization mass spectrometry (ESI MS) measurements, thus offering insight on the occurring metal-protein interactions. Notably, while carboplatin and cisplatin mainly bind the side chain of Met29, oxaliplatin also binds the side chains of Asp14, of catalytically important His119 and, to a lesser extent, of His105. On the basis of the available data, a likely mechanism for oxaliplatin hydrolysis and binding to the protein is proposed. These results are potentially useful for a better understanding of the biological chemistry, toxicity and side effects of this important class of antitumor agents.
authors.affiliation: Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy. Electronic address: luigi.messori@unifi.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.affiliation: Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Marzo
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario di Monte Sant' Angelo Via Cintia, I-80126 Napoli, Italy; CNR Institute of Biostructures and Bioimages, Via Mezzocannone 16, I-80100 Napoli, Italy. Electronic address: antonello.merlino@unina.it.
authors.forename: Antonello
authors.initials: A
authors.lastname: Merlino
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D016190:Carboplatin / Q000737:chemistry*; D002417:Cattle; D002945:Cisplatin / Q000737:chemistry; D018360:Crystallography, X-Ray; D005973:Glutamine / Q000737:chemistry; D006632:Histamine / Q000737:chemistry; D008715:Methionine / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000737:chemistry*; D000077150:Oxaliplatin; D012259:Ribonuclease, Pancreatic / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005973:Glutamine; D001224:Aspartic Acid; D006632:Histamine; D008715:Methionine; D016190:Carboplatin; D012259:Ribonuclease, Pancreatic; D002945:Cisplatin
keywords: Cancer; Mass spectrometry; Medicinal chemistry; Platinum; X-ray crystallography