Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine.
Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine.
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DOI：
10.1093/nar/gkac548
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发表时间：
2022-07-22
影响因子：
14.9
通讯作者：
Polikanov, Yury S.
中科院分区：
文献类型：
--
作者：
Syroegin, Egor A.;Aleksandrova, Elena, V;Polikanov, Yury S.
核糖体是一个通用的分子机器，能够合成细胞中的所有蛋白质。小分子抑制剂，如核糖体靶向抗生素，可以损害核糖体的催化多功能性，在一个上下文依赖的方式，防止转肽仅在特定的组合之间的基板。经典的肽基转移酶中心抑制剂氯霉素（chloramphenicol，CHL）在A位点受体底物为甘氨酸时不能抑制转肽反应，其分子基础尚不清楚。在这里，我们提出了一组高分辨率的X射线晶体结构，解释了为什么CHL不能抑制传入甘氨酰-tRNA和新生肽之间的肽键形成，否则有利于药物作用。我们的结构表明，完全容纳的甘氨酸残基可以共存于A位点与核糖体结合的CHL。此外，CHL与携带甘氨酰-tRNA的核糖体复合物的结合不影响反应底物的位置，使肽键形成反应不受干扰。这些数据说明了小分子抑制剂如何重塑A位点氨基酸结合口袋，使其仅对特定的氨基酸残基具有允许性，而对其他底物具有排斥性，从而扩展了我们对核糖体抗生素作用模式的详细理解。
Ribosome serves as a universal molecular machine capable of synthesis of all the proteins in a cell. Small-molecule inhibitors, such as ribosome-targeting antibiotics, can compromise the catalytic versatility of the ribosome in a context-dependent fashion, preventing transpeptidation only between particular combinations of substrates. Classic peptidyl transferase center inhibitor chloramphenicol (CHL) fails to inhibit transpeptidation reaction when the incoming A site acceptor substrate is glycine, and the molecular basis for this phenomenon is unknown. Here, we present a set of high-resolution X-ray crystal structures that explain why CHL is unable to inhibit peptide bond formation between the incoming glycyl-tRNA and a nascent peptide that otherwise is conducive to the drug action. Our structures reveal that fully accommodated glycine residue can co-exist in the A site with the ribosome-bound CHL. Moreover, binding of CHL to a ribosome complex carrying glycyl-tRNA does not affect the positions of the reacting substrates, leaving the peptide bond formation reaction unperturbed. These data exemplify how small-molecule inhibitors can reshape the A-site amino acid binding pocket rendering it permissive only for specific amino acid residues and rejective for the other substrates extending our detailed understanding of the modes of action of ribosomal antibiotics.
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DOI：
10.1093/toxsci/kfq085
发表时间：
2010-07
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
--
作者：
Li CH;Cheng YW;Liao PL;Yang YT;Kang JJ
通讯作者：
Kang JJ
影响因子：
3.3
作者：
Nishio, Motohiro
通讯作者：
Nishio, Motohiro
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：
4.5
作者：
Gamper, Howard;Hou, Ya-Ming
通讯作者：
Hou, Ya-Ming