Functional insights into the Streptococcus pneumoniae HicBA toxin-antitoxin system based on a structural study.
Functional insights into the Streptococcus pneumoniae HicBA toxin-antitoxin system based on a structural study.
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DOI：
10.1093/nar/gky469
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发表时间：
2018-07-06
影响因子：
14.9
通讯作者：
Lee BJ
中科院分区：
文献类型：
--
作者：
Kim DH;Kang SM;Park SJ;Jin C;Yoon HJ;Lee BJ
肺炎链球菌由于其对现有抗生素的耐药性而引起越来越多的关注。TA系统对于细菌在压力条件下的持久性是必不可少的，例如营养缺乏，抗生素治疗和免疫系统攻击。特别是S.肺炎链球菌表达HicBA TA基因，其编码稳定的HicA毒素和不稳定的HicB抗毒素。这些蛋白质在正常条件下相互作用形成无毒的TA复合物，但是毒素通过响应不利的生长条件从抗毒素释放而被激活。在这里，我们提出了第一个晶体结构显示的完整构象的HicBA复合物从S。肺炎结构表明，HicA毒素含有一个双链RNA结合域，这是必不可少的RNA识别和HicB抗毒素的C-末端折叠成一个带状螺旋螺旋DNA结合基序。HicA的活性位点被HicB的N-末端区域空间阻断。RNA酶活性测定表明，His 36是必不可少的核糖核酸酶活性的HicA，和核磁共振（NMR）光谱显示，几个残基的HicB参与结合的启动子DNA的HicBA操纵子。设计了一种能抑制TA复合物形成从而提高毒素活性的拟毒素肽，为新型抗生素的开发提供了新的途径。
Streptococcus pneumonia has attracted increasing attention due to its resistance to existing antibiotics. TA systems are essential for bacterial persistence under stressful conditions such as nutrient deprivation, antibiotic treatment, and immune system attacks. In particular, S. pneumoniae expresses the HicBA TA gene, which encodes the stable HicA toxin and the labile HicB antitoxin. These proteins interact to form a non-toxic TA complex under normal conditions, but the toxin is activated by release from the antitoxin in response to unfavorable growth conditions. Here, we present the first crystal structure showing the complete conformation of the HicBA complex from S. pneumonia. The structure reveals that the HicA toxin contains a double-stranded RNA-binding domain that is essential for RNA recognition and that the C-terminus of the HicB antitoxin folds into a ribbon-helix-helix DNA-binding motif. The active site of HicA is sterically blocked by the N-terminal region of HicB. RNase activity assays show that His36 is essential for the ribonuclease activity of HicA, and nuclear magnetic resonance (NMR) spectra show that several residues of HicB participate in binding to the promoter DNA of the HicBA operon. A toxin-mimicking peptide that inhibits TA complex formation and thereby increases toxin activity was designed, providing a novel approach to the development of new antibiotics.
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影响因子：
11.3
作者：
Chan WT;Balsa D;Espinosa M
通讯作者：
Espinosa M
影响因子：
2.9
作者：
CHEN, YH;YANG, JT;MARTINEZ, HM
通讯作者：
MARTINEZ, HM
DOI：
10.1016/j.str.2012.08.017
发表时间：
2012-10-10
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Bøggild A;Sofos N;Andersen KR;Feddersen A;Easter AD;Passmore LA;Brodersen DE
通讯作者：
Brodersen DE
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
影响因子：
3.3
作者：
Croucher NJ;Chewapreecha C;Hanage WP;Harris SR;McGee L;van der Linden M;Song JH;Ko KS;de Lencastre H;Turner C;Yang F;Sá-Leão R;Beall B;Klugman KP;Parkhill J;Turner P;Bentley SD
通讯作者：
Bentley SD