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微生物防止抗生素“自攻”的机制

蛋白-DNA结合体的复杂结构是理解机体如何防御自身抗生素的关键,也是生产商为防止菌种自毒化而规范生产的实例。某些微生物天然生产的抗生素是一个复杂而调控严密的生理过程,不只表现在微生物免受自身合成化合物的毒害作用,还表现在链球菌合成的抗生素能触发高效的泵出机制用于从细胞中输出抗生素。

SimR蛋白结合在DNA上

大部分的研究阐明了这一保护机制。SimR蛋白是链球菌用于调控抗生素输出的结构蛋白,仅能结合在DNA和抗生素其中1个上。当抗生素大量合成时,SimR释放出的DNA参与泵蛋白的编码,后者用于将抗生素泵出细胞外。

最新的研究发表在核酸研究期刊上。SimR蛋白有一个“手臂”,手臂切除后,该蛋白结合DNA的能力就降低。为了确定手臂的功能,研究人员需要得到SimR-DNA复合体的晶体结构。

他们花费3个月的时间终于找到蛋白-DNA结构的获取方法,这一方法不仅对该项目有用,还可能有益于其他人的研究。

通常情况下,SimR手臂是非结构化的,当DNA存在时,它的手臂变得有形,并结合在DNA分子的微凹槽中。晶体结构同时表明,SimR蛋白的其它部位能序列特异性地作用在泵基因的结合位点上。

 

英文摘要

The crystal structure of the TetR family transcriptional repressor SimR bound to DNA

and the role of a flexible N-terminal extension in minor groove binding

SimR, a TetR-family transcriptional regulator (TFR), controls the export of simocyclinone, a potent DNA gyrase inhibitor made by Streptomyces antibioticus. Simocyclinone is exported by a specific efflux pump, SimX and the transcription of simX is repressed by SimR, which binds to two operators in the simR-simX intergenic region. The DNA-binding domain of SimR has a classical helix-turn-helix motif, but it also carries an arginine-rich N-terminal extension. Previous structural studies showed that the N-terminal extension is disordered in the absence of DNA. Here, we show that the N-terminal extension is sensitive to protease cleavage, but becomes protease resistant upon binding DNA. We demonstrate by deletion analysis that the extension contributes to DNA binding, and describe the crystal structure of SimR bound to its operator sequence, revealing that the N-terminal extension binds in the minor groove. In addition, SimR makes a number of sequence-specific contacts to the major groove via its helix-turn-helix motif. Bioinformatic analysis shows that an N-terminal extension rich in positively charged residues is a feature of the majority of TFRs. Comparison of the SimR–DNA and SimR–simocyclinone complexes reveals that the conformational changes associated with ligand-mediated derepression result primarily from rigid-body rotation of the subunits about the dimer interface.

 

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