Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics.
Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics.
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DOI：
10.1038/s41594-022-00723-9
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发表时间：
2022-03
影响因子：
16.8
通讯作者：
Fujimori DG
中科院分区：
文献类型：
--
作者：
Tsai K;Stojković V;Lee DJ;Young ID;Szal T;Klepacki D;Vázquez-Laslop N;Mankin AS;Fraser JS;Fujimori DG
抗生素利奈唑胺是第一个临床批准的恶唑烷酮类药物，通过与肽基转移酶中心结合来抑制细菌核糖体的翻译。最近的研究表明，利奈唑胺不会抑制所有序列上的肽键形成，而是以上下文特异性方式起作用，即当丙氨酸占据新生链的倒数第二个位置时。然而，上下文特异性的分子基础尚未阐明。在这里，我们发现第二代恶唑烷酮雷德唑胺也诱导倒数第二个丙氨酸的失速，我们确定了利奈唑胺和雷德唑胺失速核糖体复合物的高分辨率cryo-EM结构，以解释其作用机制。这些结构揭示丙氨酸侧链适合于由恶唑烷酮产生的小疏水缝隙内，从而导致改善的核糖体结合。通过抗生素抗性酶Cfr对核糖体的修饰破坏了由于修饰的核苷酸的重新定位而导致的停滞。总之，我们的研究结果提供了恶唑烷酮的上下文特异性的分子理解。
The antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has demonstrated that linezolid does not inhibit peptide bond formation at all sequences but rather acts in a context-specific manner, namely when alanine occupies the penultimate position of the nascent chain. However, the molecular basis for context-specificity has not been elucidated. Here we show that the second-generation oxazolidinone radezolid also induces stalling with a penultimate alanine, and we determine high-resolution cryo-EM structures of linezolid- and radezolid-stalled ribosome complexes to explain their mechanism of action. These structures reveal that the alanine side chain fits within a small hydrophobic crevice created by oxazolidinone, resulting in improved ribosome binding. Modification of the ribosome by the antibiotic resistance enzyme Cfr disrupts stalling due to repositioning of the modified nucleotide. Together, our findings provide molecular understanding for the context-specificity of oxazolidinones.
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影响因子：
16
作者：
Leach, Karen L.;Swaney, Steven M.;Mankin, Alexander S.
通讯作者：
Mankin, Alexander S.
影响因子：
4.8
作者：
Colca, JR;McDonald, WG;Mankin, AS
通讯作者：
Mankin, AS
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：
11.8
作者：
Birmingham, MC;Rayner, CR;Schentag, JJ
通讯作者：
Schentag, JJ
影响因子：
6.4
作者：
Belousoff, Matthew J.;Eyal, Zohar;Yonath, Ada
通讯作者：
Yonath, Ada