Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state
Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state
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Madumycin II 通过迫使肽基转移酶中心进入非活性状态来抑制肽键形成
DOI：
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发表时间：
2017
影响因子：
14.9
通讯作者：
Y. Polikanov
中科院分区：
文献类型：
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作者：
I. Osterman;N. Khabibullina;E. Komarova;P. Kasatsky;V. Kartsev;A. Bogdanov;O. Dontsova;A. Konevega;P. Sergiev;Y. Polikanov
摘要多重耐药细菌的出现限制了常用抗生素的有效性，这促使人们重新关注旧的和研究不足的药物。链阳性菌素A是一类蛋白质合成抑制剂，其靶向核糖体大亚基上的肽基转移酶中心（PTC）。在这项工作中，我们揭示了PTC抑制剂madumycin II，一种含丙氨酸的链阳性菌素A抗生素，在含有tRNA底物的功能性70S核糖体的背景下的作用模式。Madumycin II在肽键形成的第一个循环之前抑制核糖体。它允许tRNA与核糖体A和P位点结合，但阻止其CCA末端正确定位到PTC中，从而使肽键形成不可能。我们还发现了一种以前未见的药物诱导的23S rRNA核苷酸U2506和U2585重排，导致形成U2506·G2583摆动对，这归因于PTC的催化失活状态。这里报道的结构和生化数据扩展了我们对肽基转移酶抑制剂调节核糖体催化活性的基本机制的认识。
Abstract The emergence of multi-drug resistant bacteria is limiting the effectiveness of commonly used antibiotics, which spurs a renewed interest in revisiting older and poorly studied drugs. Streptogramins A is a class of protein synthesis inhibitors that target the peptidyl transferase center (PTC) on the large subunit of the ribosome. In this work, we have revealed the mode of action of the PTC inhibitor madumycin II, an alanine-containing streptogramin A antibiotic, in the context of a functional 70S ribosome containing tRNA substrates. Madumycin II inhibits the ribosome prior to the first cycle of peptide bond formation. It allows binding of the tRNAs to the ribosomal A and P sites, but prevents correct positioning of their CCA-ends into the PTC thus making peptide bond formation impossible. We also revealed a previously unseen drug-induced rearrangement of nucleotides U2506 and U2585 of the 23S rRNA resulting in the formation of the U2506•G2583 wobble pair that was attributed to a catalytically inactive state of the PTC. The structural and biochemical data reported here expand our knowledge on the fundamental mechanisms by which peptidyl transferase inhibitors modulate the catalytic activity of the ribosome.
影响因子：
16
作者：
Polikanov, Yury S.;Starosta, Agata L.;Juette, Manuel F.;Altman, Roger B.;Terry, Daniel S.;Lu, Wanli;Burnett, Benjamin J.;Dinos, George;Reynolds, Kevin A.;Blanchard, Scott C.;Steitz, Thomas A.;Wilson, Daniel N.
通讯作者：
Wilson, Daniel N.
影响因子：
16
作者：
Polikanov YS;Osterman IA;Szal T;Tashlitsky VN;Serebryakova MV;Kusochek P;Bulkley D;Malanicheva IA;Efimenko TA;Efremenkova OV;Konevega AL;Shaw KJ;Bogdanov AA;Rodnina MV;Dontsova OA;Mankin AS;Steitz TA;Sergiev PV
通讯作者：
Sergiev PV