Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation.
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.
Alvarez
Hamsell M
HM
The Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA.
Xue
Yi
Y
Robinson
Chandler D
CD
Canalizo-Hernández
Mónica A
MA
Marvin
Rebecca G
RG
Kelly
Rebekah A
RA
Mondragón
Alfonso
A
Penner-Hahn
James E
JE
O'Halloran
Thomas V
TV
D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D055598:Chemical Phenomena; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D000079922:Copper Transport Proteins; D018360:Crystallography, X-Ray; D008024:Ligands; D056511:Metallochaperones / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D008982:Molybdenum / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
C093341:ATX1 protein, S cerevisiae; C092974:CCC2 protein, S cerevisiae; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D008024:Ligands; D056511:Metallochaperones; D029701:Saccharomyces cerevisiae Proteins; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate