1] Department of Physics, Indian Institute of Science, Bangalore 560012, India [2].
1] Department of Microbiology and Cell biology, Indian Institute of Science, Bangalore 560012, India [2].
Nat Commun. 2014 Jun 11;5:4124. doi: 10.1038/ncomms5124.
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.
核体相关蛋白 HU 在维持细菌染色体结构和全局调控 DNA 转译方面发挥重要作用。尽管 HU 对结核分枝杆菌（Mtb）的生长至关重要，但目前尚无报道称可以使用小分子来干扰 HU 的功能。本研究报道了 Mtb 中 HU 的 N 端结构域的晶体结构。我们在 HU-DNA 界面内鉴定出一个核心区域，可使用二苯乙烯衍生物靶向该区域。这些小分子特异性抑制 HU-DNA 结合，破坏核体结构并降低 Mtb 生长。二苯乙烯抑制剂诱导 Mtb 中基因表达的变化，与 HU 缺陷诱导的变化相似。我们的研究结果表明，HU 是开发抗结核疗法的潜在靶标。
