Inhibition of branched-chain alpha-keto acid dehydrogenase kinase and Sln1 yeast histidine kinase by the antifungal antibiotic radicicol.
The 90-kDa heat shock family (HSP90) of protein and two-component histidine kinases, although quite distinct at the primary amino acid sequence level, share a common structural ATP-binding domain known as the Bergerat fold. The Bergerat fold is important for the ATPase activity and associated chaperone function of HSP90. Two-component histidine kinases occur in bacteria, yeast, and plants but have yet to be identified in mammalian cells. The antifungal antibiotic radicicol (Monorden) has been shown to bind to the Bergerat fold of HSP90 and to inhibit its ATPase activity. The structural similarity between the Bergerat fold of HSP90 and bacterial two-component histidine kinases prompted our inquiry into whether radicicol could be a potential inhibitor of histidine kinase-like proteins. Structural homology searches suggest that the ATP-binding domains of the yeast histidine kinase Sln1 and the mammalian, branched-chain alpha-keto acid dehydrogenase kinase are very similar to that of other Bergerat fold family members. On the basis of structural homology, we tested radicicol as a potential inhibitor of Sln1 and branched-chain alpha-keto acid dehydrogenase kinase (BCKDHK) and propose a mechanism of inhibition of these kinases. Although BCKDHK has been shown to have serine autophosphorylation activity, we speculate, based on the results from this study and other supporting evidence, that BCKDHK may also have intrinsic histidine kinase activity.
Department of Medicine, University of California, San Francisco, USA. pbesant@iinet.net.au
Paul G
PG
Besant
Michael V
MV
Lasker
Cuong D
CD
Bui
Christoph W
CW
Turck
D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D015003:Yeasts / Q000187:drug effects / Q000201:enzymology
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007783:Lactones; D018942:Macrolides; D047428:Protein Kinase Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase; C083749:SLN1 protein, S cerevisiae; C035359:monorden