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Oxaliplatin Binding to Human Copper Chaperone Atox1 and Protein Dimerization

DOI: 10.1021/acs.inorgchem.6b00750 DOI Help

Authors: Benny D. Belviso (Consiglio Nazionale delle Ricerche) , Angela Galliani (Department of Chemistry, University of Bari) , Alessia Lasorsa (Department of Chemistry, University of Bari) , Valentina Mirabelli (Institute of Crystallography, Consiglio Nazionale delle Ricerche; Department of Economics, University of Foggia) , Rocco Caliandro (CNR) , Fabio Arnesano (Department of Chemistry, University of Bari) , Giovanni Natile (Department of Chemistry, University of Bari)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Inorganic Chemistry , VOL 55 , PAGES 6563 - 6573

State: Published (Approved)
Published: July 2016
Diamond Proposal Number(s): 11690

Abstract: Copper tra ffi cking proteins have been impli- cated in the cellular response to platinum anticancer drugs. We investigated the reaction of the chaperone Atox1 with an activated form of oxaliplatin, the third platinum drug to reach worldwide approval. Unlike cisplatin, which contains mono- dentate ammines, oxaliplatin contains chelated 1,2-diaminocy- clohexane (DACH), which is more resistant to displacement by nucleophiles. In solution, one or two {Pt(DACH) 2+ } moieties bind to the conserved CXXC metal-binding motif of Atox1; in the latter case the two sulfur atoms likely bridging the two platinum units. At longer reaction times, a dimeric species is formed whose composition, Atox1 2 ยท Pt 2+ 2 , indicates complete loss of the diamine ligands. Such a dimerization process is accompanied by partial unfolding of the protein. Crystallization experiments aiming at the characterization of the monomeric species have a ff orded, instead, a dimeric species resembling that already obtained by Boal and Rosenzweig in a similar reaction performed with cisplatin. However, while in the latter case there was only one Pt-binding site (0.4 occupancy) made of four sulfur atoms of the CXXC motifs of the two Atox1 chains in a tetrahedral arrangement, we found, in addition, a secondary Pt-binding site involving Cys41 of the B chain (0.25 occupancy). Moreover, both platinum atoms have lost their diamines. Thus, there appears to be little relationship between what is observed in solution and what is formed in the solid state. Since full occupancy of the tetrahedral cavity is a common feature of all Atox1 dimeric structures obtained with other metal ions (Cu + , Cd 2+ , and Hg 2+ ), we propose that in the case of platinum, where the occupancy is only 0.4, the remaining cavities are occupied by Cu + ions. Experimental evidence is reported in support of the latter hypothesis. Our proposal represents a meeting point between the initial proposal of Boal and Rosenzweig (0.4 Pt occupancy) and the reinterpretation of the original crystallographic data put forward by Shabalin et al. (1 Cu occupancy), and could apply to other cases.

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Other Facilities: ESRF