Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors
Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors
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DOI：
10.1038/ncomms5124
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发表时间：
2014-06-01
影响因子：
16.6
通讯作者：
Nagaraja, Valakunja
中科院分区：
文献类型：
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作者：
Bhowmick, Tuhin;Ghosh, Soumitra;Nagaraja, Valakunja
类核相关蛋白Hu在维持染色体结构和细菌DNA交易的全球调控中发挥着重要作用。虽然HU对于结核分枝杆菌(Mtb)的生长是必不可少的，但还没有报道试图用小分子来干扰HU的功能。在这里，我们报道了Mtb中HU的N-末端结构域的晶体结构。我们确定了Hu-DNA界面内的一个核心区域，该区域可以用二苯乙烯类衍生物作为靶点。这些小分子特异性地抑制HU-DNA结合，破坏类核结构，减少结核分枝杆菌的生长。二苯乙烯类抑制剂诱导Mtb的基因表达变化，类似于HU缺乏引起的变化。我们的结果表明，HU是开发抗结核治疗的潜在靶点。
The nucleoid-associated protein HU plays an important role in maintenance of chromosomal architecture and in global regulation of DNA transactions in bacteria. Although HU is essential for growth in Mycobacterium tuberculosis (Mtb), there have been no reported attempts to perturb HU function with small molecules. Here we report the crystal structure of the N-terminal domain of HU from Mtb. We identify a core region within the HU-DNA interface that can be targeted using stilbene derivatives. These small molecules specifically inhibit HU-DNA binding, disrupt nucleoid architecture and reduce Mtb growth. The stilbene inhibitors induce gene expression changes in Mtb that resemble those induced by HU deficiency. Our results indicate that HU is a potential target for the development of therapies against tuberculosis.