Inhibition of branched-chain α-keto acid dehydrogenase kinase and Sln1 yeast histidine kinase by the antifungal antibiotic radicicol
Inhibition of branched-chain α-keto acid dehydrogenase kinase and Sln1 yeast histidine kinase by the antifungal antibiotic radicicol
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DOI：
10.1124/mol.62.2.289
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发表时间：
2002-08-01
影响因子：
3.6
通讯作者：
Turck, CW
中科院分区：
文献类型：
--
作者：
Besant, PG;Lasker, MV;Turck, CW
90 kDa热休克蛋白家族(HSP90)由蛋白质和两组分组氨酸组成，虽然在初级氨基酸序列水平上有很大的不同，但它们有一个共同的结构ATP结合结构域，称为Bergerat折叠。Bergerat折叠对于HSP90的ATPase活性和相关的伴侣功能是重要的。在细菌、酵母和植物中存在双组分组氨酸激酶，但在哺乳动物细胞中尚未确定。抗真菌抗生素自由基(Monorden)已被证明与HSP90的Bergerat折叠结合并抑制其ATPase活性。HSP90的Bergerat折叠与细菌双组分组氨酸激酶之间的结构相似性促使我们探讨自由基醇是否可能是组氨酸激酶样蛋白的潜在抑制剂。结构同源性搜索表明，酵母组氨酸激酶SLn1和哺乳动物支链α-酮酸脱氢酶激酶的ATP结合域与Bergerat折叠家族的其他成员非常相似。在结构同源性的基础上，我们测试了自由基作为SLn1和支链α-酮酸脱氢酶激酶(BCKDHK)的潜在抑制剂，并提出了抑制这些激酶的机制。尽管BCKDHK已被证明具有丝氨酸自磷酸化活性，但根据本研究的结果和其他支持证据，我们推测BCKDHK可能也具有内在的组氨酸激酶活性。
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.