Role of PemI in the Staphylococcus aureus PemIK toxin-antitoxin complex: PemI controls PemK by acting as a PemK loop mimic.
Role of PemI in the Staphylococcus aureus PemIK toxin-antitoxin complex: PemI controls PemK by acting as a PemK loop mimic.
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DOI：
10.1093/nar/gkab1288
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发表时间：
2022-02-28
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;Baek SM;Yoon HJ;Jang DM;Kim HS;Lee SJ;Lee BJ
金黄色葡萄球菌（Staphylococcus aureus）是一种臭名昭著的全球性致病菌。基于细菌内毒素-抗毒素（TA）系统开发新型抗生素的新策略最近已被报道。由于TA系统仅存在于细菌中而不存在于人类中，因此这些独特的系统是开发具有新作用模式的抗生素的有吸引力的目标。S.金黄色葡萄球菌PemIK是II型TA系统，包括毒素蛋白PemK和不稳定抗毒素蛋白PemI。在这里，我们确定了PemK和PemIK复合物的晶体结构，其中PemK被PemI中和。我们的生物化学方法，包括荧光猝灭和偏振测定，确定Glu 20，Arg 25，Thr 48，Thr 49和Arg 84的PemK作为重要的RNase功能。我们的研究表明，PemK的活性位点和RNA结合残基被PemI覆盖，导致PemK独特的构象变化，伴随着β1和β2之间的环的重新定位。这些变化可以干扰PemK与RNA的结合。总的来说，PemK采用特定的开放和封闭形式，以实现PemI的精确中和。PemIK的结构和功能信息将有助于发现和开发抑制PemI和PemK之间直接结合的肽或小分子形式的新型抗生素。
Staphylococcus aureus is a notorious and globally distributed pathogenic bacterium. New strategies to develop novel antibiotics based on intrinsic bacterial toxin–antitoxin (TA) systems have been recently reported. Because TA systems are present only in bacteria and not in humans, these distinctive systems are attractive targets for developing antibiotics with new modes of action. S. aureus PemIK is a type II TA system, comprising the toxin protein PemK and the labile antitoxin protein PemI. Here, we determined the crystal structures of both PemK and the PemIK complex, in which PemK is neutralized by PemI. Our biochemical approaches, including fluorescence quenching and polarization assays, identified Glu20, Arg25, Thr48, Thr49, and Arg84 of PemK as being important for RNase function. Our study indicates that the active site and RNA-binding residues of PemK are covered by PemI, leading to unique conformational changes in PemK accompanied by repositioning of the loop between β1 and β2. These changes can interfere with RNA binding by PemK. Overall, PemK adopts particular open and closed forms for precise neutralization by PemI. This structural and functional information on PemIK will contribute to the discovery and development of novel antibiotics in the form of peptides or small molecules inhibiting direct binding between PemI and PemK.
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细菌程序性细胞死亡和细菌多细胞行为。
影响因子：
4.5
作者：
通讯作者：
--
影响因子：
4.5
作者：
Kang SM;Moon H;Han SW;Kim BW;Kim DH;Kim BM;Lee BJ
通讯作者：
Lee BJ
影响因子：
7.3
作者：
Kang, Sung-Min;Jin, Chenglong;Lee, Bong-Jin
通讯作者：
Lee, Bong-Jin
影响因子：
5.6
作者：
Kamphuis, MB;Bonvin, AMJJ;Boelens, R
通讯作者：
Boelens, R
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