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Tetrathiomolybdate Inhibits Copper Trafficking Proteins Through Metal Cluster Formation

Science  15 Jan 2010:
Vol. 327, Issue 5963, pp. 331-334
DOI: 10.1126/science.1179907

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Targeting Copper Clusters

Tetrathiomolybdate (TM) is a copper-depleting agent that has potential in treating copper-dependent diseases. Alvarez et al. (p. 331, published online 26 November) used spectroscopic and structural studies to show that TM inhibits the yeast copper chaperone Atx1 by forming a TM-Cu-ATx1 complex that is stabilized by a sulfur-bridged copper-molybdenum cluster. Cluster formation prevents transfer of copper from the chaperone to target enzymes. The results provide a basis for developing drugs that target metallation pathways.

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.

  • * These authors contributed equally to this work.

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