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首页> 外文期刊>Nucleic acids research >Structural insights into the function of aminoglycoside-resistance A1408 16S rRNA methyltransferases from antibiotic-producing and human pathogenic bacteria
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Structural insights into the function of aminoglycoside-resistance A1408 16S rRNA methyltransferases from antibiotic-producing and human pathogenic bacteria

机译：产生抗生素和人类致病菌对氨基糖苷抗性A1408 16S rRNA甲基转移酶功能的结构洞察

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X-ray crystal structures were determined of the broad-spectrum aminoglycoside-resistance A1408 16S rRNA methyltransferases KamB and NpmA, from the aminoglycoside-producer Streptoalloteichus tenebrarius and human pathogenic Escherichia coli, respectively. Consistent with their common function, both are Class I methyltransferases with additional highly conserved structural motifs that embellish the core SAM-binding fold. In overall structure, the A1408 rRNA methyltransferase were found to be most similar to a second family of Class I methyltransferases of distinct substrate specificity (m7G46 tRNA). Critical residues for A1408 rRNA methyltransferase activity were experimentally defined using protein mutagenesis and bacterial growth assays with kanamycin. Essential residues for SAM coenzyme binding and an extended protein surface that likely interacts with the 30S ribosomal subunit were thus revealed. The structures also suggest potential mechanisms of A1408 target nucleotide selection and positioning. We propose that a dynamic extended loop structure that is positioned adjacent to both the bound SAM and a functionally critical structural motif may mediate concerted conformational changes in rRNA and protein that underpin the specificity of target selection and activation of methyltransferase activity. These new structures provide important new insights that may provide a starting point for strategies to inhibit these emerging causes of pathogenic bacterial resistance to aminoglycosides.
机译：X射线晶体结构分别测定了来自氨基糖苷生产商的Streptoalloteichus tenebrarius和人类病原性大肠杆菌的广谱氨基糖苷耐药性A1408 16S rRNA甲基转移酶KamB和NpmA。与它们的共同功能一致，两者都是具有额外高度保守的结构基序的I类甲基转移酶，这些基序修饰了核心SAM结合折叠。在总体结构上，发现A1408 rRNA甲基转移酶与具有不同底物特异性（m 7 G46 tRNA）的第二类I类甲基转移酶最为相似。使用蛋白诱变和卡那霉素细菌生长试验，通过实验确定了A1408 rRNA甲基转移酶活性的关键残基。因此揭示了SAM辅酶结合的必需残基和可能与30S核糖体亚基相互作用的延伸蛋白表面。该结构还暗示了A1408靶核苷酸选择和定位的潜在机制。我们建议，位于与绑定的SAM和功能关键的结构基序都相邻的动态扩展环结构可以介导rRNA和蛋白质中一致的构象变化，从而支持目标选择和甲基转移酶活性的特异性。这些新结构提供了重要的新见解，可为抑制致病性细菌对氨基糖苷耐药性的这些新兴原因的策略提供起点。

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