Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30643139.
- Also identified by DOI 10.1038/s41467-018-08102-z and PMC identifier 6331642.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson's disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo<sub>2</sub>S<sub>6</sub>O<sub>2</sub> cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins.
Medical subject headings
- Antineoplastic Agents
- Chelating Agents
- Cisplatin
- Copper-Transporting ATPases
- Molybdenum