PIF-pocket as a target for C. albicans Pkh selective inhibitors.
PIF-pocket as a target for C. albicans Pkh selective inhibitors.
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PIF袋作为白色念珠菌Pkh选择性抑制剂的靶点
DOI：
10.1021/cb400452z
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发表时间：
2013
影响因子：
4
通讯作者：
Biondi RM
中科院分区：
文献类型：
--
作者：
Pastor-Flores D;Schulze JO;Bahí A;Giacometti R;Ferrer-Dalmau J;Passeron S;Engel M;Suess E;Casamayor A;Biondi RM
磷酸肌醇依赖性蛋白激酶1（PDK 1）是一种主激酶，可使多达23种AGC激酶的激活环磷酸化。S.酿酒酵母具有三个PDK 1直向同源物，Pkh 1 -3，其也磷酸化AGC激酶（例如，Ypk、Tpk、Pkc 1和Sch 9）。PKH 1和PKH 2是参与多种基本细胞功能的冗余蛋白，包括内吞作用和细胞壁完整性。基于与芽殖酵母的相似性，真菌传染性物种的Pkh被假定为抗真菌药物的新靶点。在这里，我们发现Pkh的耗尽最终诱导氧化应激和DNA双链断裂，导致程序性细胞死亡。这一发现支持Pkh作为抗真菌靶点，因为Pkh的药理学抑制将导致酵母细胞死亡，这是抗真菌药的最终目标。因此，进一步研究开发对念珠菌Pkh具有选择性的Pkh抑制剂的可能性是有意义的，该抑制剂不会抑制人类直系同源物。在这里，我们描述C。白色念珠菌Pkh 2的生物化学、结构和使用化学探针与人PDK 1进行比较。我们发现C.白色念珠菌Pkh 2催化结构域，PIF口袋，从人PDK 1发散。事实上，我们鉴定和表征了PS 77，一种新的针对PIF口袋的小变构抑制剂，它增加了对C.白色念珠菌Pkh 2.总之，我们的研究结果描述了PKH生物学和化学生物学方法的新特征，这些方法支持PKH作为选择性抗真菌药物的药物靶点的验证。
The phosphoinositide-dependent protein kinase 1, PDK1, is a master kinase that phosphorylates the activation loop of up to 23 AGC kinases. S. cerevisiae has three PDK1 orthologues, Pkh1–3, which also phosphorylate AGC kinases (e.g., Ypk, Tpk, Pkc1, and Sch9). Pkh1 and 2 are redundant proteins involved in multiple essential cellular functions, including endocytosis and cell wall integrity. Based on similarities with the budding yeast, the Pkh of fungal infectious species was postulated as a novel target for antifungals. Here, we found that depletion of Pkh eventually induces oxidative stress and DNA double-strand breaks, leading to programmed cell death. This finding supports Pkh as an antifungal target since pharmacological inhibition of Pkh would lead to the death of yeast cells, the ultimate goal of antifungals. It was therefore of interest to further investigate the possibility to develop Pkh inhibitors with selectivity for Candida Pkh that would not inhibit the human ortholog. Here, we describe C. albicans Pkh2 biochemically, structurally and by using chemical probes in comparison to human PDK1. We found that a regulatory site on the C. albicans Pkh2 catalytic domain, the PIF-pocket, diverges from human PDK1. Indeed, we identified and characterizedPS77, a new small allosteric inhibitor directed to the PIF-pocket, which has increased selectivity for C. albicans Pkh2. Together, our results describe novel features of the biology of Pkh and chemical biology approaches that support the validation of Pkh as a drug target for selective antifungals.
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影响因子：
11.4
作者：
Biondi, RM;Cheung, PCF;Alessi, DR
通讯作者：
Alessi, DR
影响因子：
4.8
作者：
Luo, Guangzuo;Costanzo, Michael;Dickson, Robert C.
通讯作者：
Dickson, Robert C.
影响因子：
14.8
作者：
Hindie, Valerie;Stroba, Adriana;Biondi, Ricardo M.
通讯作者：
Biondi, Ricardo M.
影响因子：
11.2
作者：
Z. Zeng;I. Samudio;Weiguo Zhang;Z. Estrov;H. Pelicano;D. Harris;O. Frolova;N. Hail;Wenjing Chen-Wenji
通讯作者：
Z. Zeng;I. Samudio;Weiguo Zhang;Z. Estrov;H. Pelicano;D. Harris;O. Frolova;N. Hail;Wenjing Chen-Wenji
酿酒酵母中的蛋白酶和半胱天冬酶样活性。
影响因子：
3.9
作者：
Derek Wilkinson;M. Ramsdale
通讯作者：
M. Ramsdale