Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase.
Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase.
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DOI：
10.1038/ncomms7402
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发表时间：
2015-03-31
影响因子：
16.6
通讯作者：
Guo, Min
中科院分区：
文献类型：
--
作者：
Fang, Pengfei;Yu, Xue;Jeong, Seung Jae;Mirando, Adam;Chen, Kaige;Chen, Xin;Kim, Sunghoon;Francklyn, Christopher S.;Guo, Min
聚酮化合物天然产物疏螺旋体素通过选择性抑制苏氨酰-tRNA合成酶（ThrRS）而显示出抗细菌、抗真菌、抗疟疾、抗癌、杀虫和除草活性。疏螺旋体素如何同时减弱细菌生长并抑制植物和动物中的各种感染尚不清楚。在这里，我们表明，使用X-射线晶体结构和功能分析，一个单一的疏螺旋体素分子同时占据细菌和人类ThrRSs的催化结构域内的四个不同的亚位点。这些包括与氨酰化相关的氨基酸、ATP和tRNA的三个底物结合位点，以及由于结合而产生的第四个“正交”亚位点。因此，疏螺旋体素与所有三种氨酰化底物竞争，提供了在蛋白质合成期间抑制ThrRS的有效和冗余机制。这些结果突出了通过高度保守的酶家族实现翻译的四价抑制的令人惊讶的天然设计。 疏螺旋体素是一种具有抗微生物、抗真菌、抗疟疾和免疫抑制活性的抗生素，靶向苏氨酰-tRNA合成酶。在这里，作者表明疏螺旋体素通过阻止所有三种ThrRS底物的结合并诱导酶的独特的非生产性构象来发挥作用。
The polyketide natural product borrelidin displays antibacterial, antifungal, antimalarial, anticancer, insecticidal and herbicidal activities through the selective inhibition of threonyl-tRNA synthetase (ThrRS). How borrelidin simultaneously attenuates bacterial growth and suppresses a variety of infections in plants and animals is not known. Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth ‘orthogonal’ subsite created as a consequence of binding. Thus, borrelidin competes with all three aminoacylation substrates, providing a potent and redundant mechanism to inhibit ThrRS during protein synthesis. These results highlight a surprising natural design to achieve the quadrivalent inhibition of translation through a highly conserved family of enzymes. Borrelidin is an antibiotic with antimicrobial, antifungal, antimalarial and immunosuppressive activity that targets threonyl-tRNA synthetase. Here the authors show that borrelidin functions by preventing binding of all three ThrRS substrates and inducing a distinct, non-productive, conformation of the enzyme.
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影响因子：
14.8
作者：
Keller, Tracy L.;Zocco, Davide;Sundrud, Mark S.;Hendrick, Margaret;Edenius, Maja;Yum, Jinah;Kim, Yeon-Jin;Lee, Hak-Kyo;Cortese, Joseph F.;Wirth, Dyann F.;Dignam, John David;Rao, Anjana;Yeo, Chang-Yeol;Mazitschek, Ralph;Whitman, Malcolm
通讯作者：
Whitman, Malcolm
影响因子：
3.4
作者：
Habibi, Darya;Ogloff, Nadya;Ong, Christopher J.
通讯作者：
Ong, Christopher J.
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：
64.8
作者：
DICKINSON, L;GRIFFITHS, AJ;MILLS, RFN
通讯作者：
MILLS, RFN
影响因子：
56.9
作者：
BELRHALI, H;YAREMCHUK, A;CUSACK, S
通讯作者：
CUSACK, S