Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation

Hamsell M. Alvarez, Yi Xue, Chandler D. Robinson, Mónica A. Canalizo-Hernández, Rebecca G. Marvin, Rebekah A. Kelly, Alfonso Mondragón, James E. Penner-Hahn, Thomas V. O'Halloran

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

Tetrathiomolybdate (TM) is an orally active agent for treatment of disorders of copper metabolism. Here we describe how TM inhibits proteins that regulate copper physiology. Crystallographic results reveal that the surprising stability of the drug complex with the metallochaperone Atx1 arises from formation of a sulfur-bridged copper-molybdenum cluster reminiscent of those found in molybdenum and iron sulfur proteins. Spectroscopic studies indicate that this cluster is stable in solution and corresponds to physiological clusters isolated from TM-treated Wilson's disease animal models. Finally, mechanistic studies show that the drug-metallochaperone inhibits metal transfer functions between copper-trafficking proteins. The results are consistent with a model wherein TM can directly and reversibly down-regulate copper delivery to secreted metalloenzymes and suggest that proteins involved in metal regulation might be fruitful drug targets.

Original languageEnglish (US)
Pages (from-to)331-334
Number of pages4
JournalScience
Volume327
Issue number5963
DOIs
StatePublished - Jan 15 2010

ASJC Scopus subject areas

  • General

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