Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons.
Structure of the master regulator Rns reveals an inhibitor of enterotoxigenic Escherichia coli virulence regulons.
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DOI：
10.1038/s41598-021-95123-2
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发表时间：
2021-08-02
影响因子：
4.6
通讯作者：
Kull FJ
中科院分区：
文献类型：
--
作者：
Midgett CR;Talbot KM;Day JL;Munson GP;Kull FJ
由革兰氏阴性细菌肠致病性大肠杆菌（ETEC）、霍乱弧菌、福氏志贺菌和肠道沙门氏菌引起的肠道感染是最常见的，每年影响数十亿人。这些细菌使用转录调节因子的网络来控制毒力因子的表达，其中一些转录调节因子由小分子调节，如已经显示的ToxT，来自霍乱弧菌的AraC家族成员。在ETEC中，许多类型的粘附皮利的表达依赖于AraC家族成员Rns。我们在这里提出的Rns的3 π晶体结构，并显示它非常类似于ToxT。Rns通过类似于在其他二聚体AraC中观察到的界面结晶为二聚体。此外，Rns的结构揭示了配体癸酸的存在，其以类似于对ToxT和S.肠同源菌HilD.总之，这些结果支持我们的假设，脂肪酸调节毒力控制AraC家族成员在一个共同的方式在许多肠道病原体。此外，这项工作首次确定了一种能够抑制ETEC Rns调节子的小分子，为开发针对这种致命的人类病原体的治疗方法提供了基础。
Enteric infections caused by the gram-negative bacteria enterotoxigenic Escherichia coli (ETEC), Vibrio cholerae, Shigella flexneri, and Salmonella enterica are among the most common and affect billions of people each year. These bacteria control expression of virulence factors using a network of transcriptional regulators, some of which are modulated by small molecules as has been shown for ToxT, an AraC family member from V. cholerae. In ETEC the expression of many types of adhesive pili is dependent upon the AraC family member Rns. We present here the 3 Å crystal structure of Rns and show it closely resembles ToxT. Rns crystallized as a dimer via an interface similar to that observed in other dimeric AraC’s. Furthermore, the structure of Rns revealed the presence of a ligand, decanoic acid, that inhibits its activity in a manner similar to the fatty acid mediated inhibition observed for ToxT and the S. enterica homologue HilD. Together, these results support our hypothesis that fatty acids regulate virulence controlling AraC family members in a common manner across a number of enteric pathogens. Furthermore, for the first time this work identifies a small molecule capable of inhibiting the ETEC Rns regulon, providing a basis for development of therapeutics against this deadly human pathogen.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.9
作者：
Cruite, Justin T.;Kovacikova, Gabriela;Kull, F. Jon
通讯作者：
Kull, F. Jon
影响因子：
7.1
作者：
CASPARY, WF
通讯作者：
CASPARY, WF
影响因子：
4.2
作者：
Bodero, Maria D.;Harden, Elizabeth A.;Munson, George P.
通讯作者：
Munson, George P.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH