Tetrathiomolybdate Inhibits Copper Trafficking Proteins Through Metal Cluster Formation

被引：146

作者：

Alvarez, Hamsell M. ^{[1
]}

Xue, Yi ^{[1
]}

Robinson, Chandler D. ^{[1
]}

Canalizo-Hernandez, Monica A. ^{[1
]}

Marvin, Rebecca G. ^{[1
]}

Kelly, Rebekah A. ^{[3
]}

Mondragon, Alfonso ^{[2
]}

Penner-Hahn, James E. ^{[3
]}

O'Halloran, Thomas V. ^{[1
,2
]}

机构：

[1] Northwestern Univ, Chem Life Proc Inst, Evanston, IL 60208 USA

[2] Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA

[3] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA

来源：

SCIENCE | 2010年 / 327卷 / 5963期

基金：

美国国家航空航天局;

关键词：

WILSONS-DISEASE; ATX1; METALLOCHAPERONE; CELL-PROLIFERATION; SUPEROXIDE-DISMUTASE-1; THIOMOLYBDATE; ANGIOGENESIS; RESOLUTION; THERAPY; GROWTH; CANCER;

D O I：

10.1126/science.1179907

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：331 / 334

页数：4

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