Publication Date:
2009-12-08
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658115/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658115/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alvarez, Hamsell M -- Xue, Yi -- Robinson, Chandler D -- Canalizo-Hernandez, Monica A -- Marvin, Rebecca G -- Kelly, Rebekah A -- Mondragon, Alfonso -- Penner-Hahn, James E -- O'Halloran, Thomas V -- GM38047/GM/NIGMS NIH HHS/ -- GM38784/GM/NIGMS NIH HHS/ -- GM54222/GM/NIGMS NIH HHS/ -- R01 GM038047/GM/NIGMS NIH HHS/ -- R01 GM038784/GM/NIGMS NIH HHS/ -- R01 GM054111/GM/NIGMS NIH HHS/ -- R37 GM038784/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2010 Jan 15;327(5963):331-4. doi: 10.1126/science.1179907. Epub 2009 Nov 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19965379" target="_blank"〉PubMed〈/a〉
Keywords:
Carrier Proteins/*antagonists & inhibitors/chemistry/*metabolism
;
Cation Transport Proteins/metabolism
;
Copper/chemistry/*metabolism
;
Crystallography, X-Ray
;
Ligands
;
Metallochaperones/*antagonists & inhibitors/chemistry/*metabolism
;
Models, Chemical
;
Models, Molecular
;
Molecular Structure
;
Molybdenum/chemistry/*metabolism/*pharmacology
;
Oxidation-Reduction
;
Physicochemical Processes
;
Protein Conformation
;
Saccharomyces cerevisiae Proteins/*antagonists & inhibitors/chemistry/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
