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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 and Thomas V. O'Halloran
New Series, Vol. 327, No. 5963 (Jan. 15, 2010), pp. 331-334
Published by: American Association for the Advancement of Science
Stable URL: http://www.jstor.org/stable/40508536
Page Count: 4
You can always find the topics here!Topics: Copper, Atoms, Sulfides, Gels, Trimers, Molybdenum, Monomers, Sulfur, Hepatolenticular degeneration, Enzymes
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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.
Science © 2010 American Association for the Advancement of Science