Structural basis for TetM-mediated tetracycline resistance
Structural basis for TetM-mediated tetracycline resistance
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DOI：
10.1073/pnas.1208037109
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发表时间：
2012-10-16
影响因子：
11.1
通讯作者：
Wilson, Daniel N.
中科院分区：
文献类型：
--
作者：
Doenhoefer, Alexandra;Franckenberg, Sibylle;Wilson, Daniel N.
核糖体保护蛋白（RPPs）通过与核糖体结合并将药物从其结合位点追赶而赋予四环素耐药性。目前关于RPP作用机制的模型提出，药物释放是间接的，是通过RPP与核糖体结合引起的药物结合位点的构象变化来实现的。本文报道了RPP TetM与70S核糖体复合物在7.2埃分辨率下的低温电镜结构。该结构揭示了TetM与核糖体的接触，包括TetM的保守和功能关键的c端扩展与小亚基解码中心之间的相互作用。此外，我们观察到TetM的结构域IV与四环素结合位点之间的直接相互作用，并确定了赋予四环素抗性的关键残基。提出了一种模型，即TetM直接排出四环素以赋予耐药性。
Ribosome protection proteins (RPPs) confer tetracycline resistance by binding to the ribosome and chasing the drug from its binding site. The current model for the mechanism of action of RPPs proposes that drug release is indirect and achieved via conformational changes within the drug-binding site induced upon binding of the RPP to the ribosome. Here we report a cryo-EM structure of the RPP TetM in complex with the 70S ribosome at 7.2-angstrom resolution. The structure reveals the contacts of TetM with the ribosome, including interaction between the conserved and functionally critical C-terminal extension of TetM and the decoding center of the small subunit. Moreover, we observe direct interaction between domain IV of TetM and the tetracycline binding site and identify residues critical for conferring tetracycline resistance. A model is presented whereby TetM directly dislodges tetracycline to confer resistance.