Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 53, Issue 5, Pages 1297-1301Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201307718
Keywords
ATPases; charge measurements; copper; NMR spectroscopy; platinum drugs
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Funding
- University of Bari
- University of Florence
- Ente Cassa di Risparmio di Firenze
- Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB)
- Italian Ministero dell'Universita e della Ricerca [PON 01078, PRIN 2010M2JARJ, PRIN 2009WCNS5C, PON01_00937, PRIN 20083YM37E]
- European Commission (COST Actions) [CM0902, CM1105]
- USA National Institutes of Health, NHLBI [RO301-69830]
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Cisplatin, carboplatin, and oxaliplatin are widely used anticancer drugs. Their efficacy is strongly reduced by development of cell resistance. Down-regulation of CTR1 and up-regulation of the Cu-ATPases, ATP7A and ATP7B, have been associated to augmented drug resistance. To gain information on translocation of Pt drugs by human Cu-ATPases, we performed electrical measurements on the COS-1 cell microsomal fraction, enriched with recombinant ATP7A, ATP7B, and selected mutants, and adsorbed on a solid supported membrane. The experimental results indicate that Pt drugs activate Cu-ATPases and undergo ATP-dependent translocation in a fashion similar to that of Cu. We then used NMR spectroscopy and ESI-MS to determine the binding mode of these drugs to the first N-terminal metal-binding domain of ATP7A (Mnk1).
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