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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity
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Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity

机译：诱导拟合可增强截短侧耳素与核糖体的结合，而远程相互作用可使其选择性

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摘要

New insights into functional flexibility at the peptidyl transferase center (PTC) and its vicinity were obtained by analysis of pleuromutilins binding modes to the ribosome. The crystal structures of Deino-coccus radiodurans large ribosomal subunit complexed with each of three pleuromutilin derivatives: retapamulin (SB-275833), SB-280080, and SB-571519, show that all bind to the PTC with their core oriented similarly at the A-site and their C14 extensions pointing toward the P-site. Except for an H-bond network with a single nucleotide, G2061, which involves the essential keto group of all three compounds, only minor hydrophobic contacts are formed between the pleuromutilin C14 extensions and any ribosomal component, consistent with the PTC tolerance to amino acid diversity. Efficient drug binding mode is attained by a mechanism based on induced-fit motions exploiting the ribosomal intrinsic functional flexibility and resulting in conformational rearrangements that seal the pleuromutilin-binding pocket and tightens it up. Comparative studies identified a network of remote interactions around the PTC, indicating that pleuromutilins selectivity is acquired by nonconserved nucleotides residing in the PTC vicinity, in a fashion resembling allosterism. Likewise, pleuromutilin resistant mechanisms involve nucleotides residing in the environs of the binding pocket, consistent with their slow resistance-development rates.
机译：通过分析截短侧耳素与核糖体的结合模式，获得了对肽基转移酶中心（PTC）及其附近功能灵活性的新见解。 Deino-coccus radiodurans大核糖体亚基的晶体结构与三种截短侧耳素衍生物（retapamulin（SB-275833），SB-280080和SB-571519）均复合，表明它们均与PTC结合，其核心类似地位于A处。站点及其指向P站点的C14扩展名。除了具有单个核苷酸的H-键网络G2061（涉及所有三个化合物的必不可少的酮基）外，截短侧耳素C14延伸片段和任何核糖体成分之间仅形成少量疏水接触，这与PTC对氨基酸多样性的耐受性相一致。高效的药物结合模式是通过一种基于诱导拟合运动的机制来实现的，该机制利用了核糖体固有的功能灵活性并导致构象重排，从而密封了截短侧耳素结合袋并使其紧紧。比较研究确定了PTC周围的远程相互作用网络，这表明截短侧耳素的选择性是通过位于PTC附近的非保守核苷酸以类似于变构的方式获得的。同样，截短侧耳素抗性机制涉及存在于结合袋周围的核苷酸，这与其缓慢的耐药性发展速度相一致。

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