Insights into the molecular mechanism of translation inhibition by the ribosome-targeting antibiotic thermorubin.
Insights into the molecular mechanism of translation inhibition by the ribosome-targeting antibiotic thermorubin.
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DOI：
10.1093/nar/gkac1189
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发表时间：
2023-01-11
影响因子：
14.9
通讯作者：
Gagnon, Matthieu G.
中科院分区：
文献类型：
--
作者：
Paranjpe, Madhura N.;Marina, Valeria, I;Grachev, Aleksandr A.;Maviza, Tinashe P.;Tolicheva, Olga A.;Paleskava, Alena;Osterman, Ilya A.;Sergiev, Petr, V;Konevega, Andrey L.;Polikanov, Yury S.;Gagnon, Matthieu G.
嗜热菌红素（THR）是一种芳香族蒽并吡喃酮抗生素，对革兰氏阳性和革兰氏阴性细菌都有活性。已知其在亚基间桥B2 a处与70 S核糖体结合，并被认为抑制因子依赖性翻译起始并阻碍tRNA进入A位点。在这里，我们表明，嗜热红蛋白导致核糖体在体内和体外停滞在内部和终止密码子，从而允许核糖体启动蛋白质合成和翻译至少几个密码子之前失速。我们的生化数据表明，THR影响翻译延伸的多个步骤，对A位点中tRNA的结合稳定性有显著影响，解释了翻译的过早停止。我们的70 S-THR复合物的高分辨率晶体和冷冻电镜结构表明，THR可以与P-和A-位点tRNA共存，解释了核糖体如何在药物存在下伸长。值得注意的是THR在终止密码子处阻止核糖体的能力。我们的数据表明，通过引起解码中心的结构重排，THR干扰tRNA或释放因子进入核糖体A位点的调节。
Thermorubin (THR) is an aromatic anthracenopyranone antibiotic active against both Gram-positive and Gram-negative bacteria. It is known to bind to the 70S ribosome at the intersubunit bridge B2a and was thought to inhibit factor-dependent initiation of translation and obstruct the accommodation of tRNAs into the A site. Here, we show that thermorubin causes ribosomes to stall in vivo and in vitro at internal and termination codons, thereby allowing the ribosome to initiate protein synthesis and translate at least a few codons before stalling. Our biochemical data show that THR affects multiple steps of translation elongation with a significant impact on the binding stability of the tRNA in the A site, explaining premature cessation of translation. Our high-resolution crystal and cryo-EM structures of the 70S-THR complex show that THR can co-exist with P- and A-site tRNAs, explaining how ribosomes can elongate in the presence of the drug. Remarkable is the ability of THR to arrest ribosomes at the stop codons. Our data suggest that by causing structural re-arrangements in the decoding center, THR interferes with the accommodation of tRNAs or release factors into the ribosomal A site.
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DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
影响因子：
4.5
作者：
Konevega, AL;Soboleva, NG;Katunin, VI
通讯作者：
Katunin, VI
影响因子：
64.8
作者：
Mitcheltree, Matthew J.;Pisipati, Amarnath;Myers, Andrew G.
通讯作者：
Myers, Andrew G.
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：
64.8
作者：
Laurberg, Martin;Asahara, Haruichi;Noller, Harry F.
通讯作者：
Noller, Harry F.