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首页> 外文期刊>Journal of Molecular Biology >Structural and Functional Plasticity of Antibiotic Resistance Nucleotidylyltransferases Revealed by Molecular Characterization of Lincosamide Nucleotidylyltransferases Lnu(A) and Lnu(D)
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Structural and Functional Plasticity of Antibiotic Resistance Nucleotidylyltransferases Revealed by Molecular Characterization of Lincosamide Nucleotidylyltransferases Lnu(A) and Lnu(D)

机译：林考酰胺核糖基转移酶Lnu（A）和Lnu（D）的分子表征揭示了抗生素抗性核糖基转移酶的结构和功能可塑性。

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One of the main mechanisms of resistance to lincosamide and aminoglycoside antibiotics is their inactivation by O-nucleotidylyltransferases (NTases). Significant sequence variation of lincomycin nucleotidylyltransferase (Lnu) and aminoglycoside nucleotidylyltransferase (ANT) enzymes plus lack of detailed information about the molecular basis for specificity of these enzymes toward chemically distinct antibiotic scaffolds hinders development of a general strategy to curb this resistance mechanism. We conducted an extensive sequence analysis identifying 129 putative antibiotic NTases constituting six distinct subfamilies represented by Lnu(A), Lnu(B), Lnu(C), Lnu(D), Lnu(F)/(G) plus ANT(2") enzymes. Since only the Lnu(B) enzyme has been previously studied in detail, we biochemically characterized the Lnu(A) and Lnu(D) enzymes, with the former representing the most sequence distinct Lnu ortholog. We also determined the crystal structure of the Lnu(A) enzyme in complex with a lincosamide. These data suggested that, while sharing the N-terminal nucleotidylyltransferase domain, the groups of antibiotic NTases feature structurally distinct C-terminal domains (CTDs) adapted to accommodate antibiotics. Comparative structural analysis among antibiotic NTases rationalized their specificity toward lincosamides versus aminoglycosides through active-site plasticity, which allows retention of general catalytic activity while accepting alterations at multiple, specific positions contributed by both domains. Based on this structural analysis, we suggest that antibiotic NTases evolved from an ancestral nucleotidylyltransferase along independent paths according to the identified groups, characterized by structural changes in the active site and recruitment of structurally diverse CTDs. These data show the complexity of enzyme-driven antibiotic resistance and provide a basis for broadly active inhibitors by identifying the key unifying features of antibiotic NTases. (C) 2015 Elsevier Ltd. All rights reserved.
机译：对林可酰胺和氨基糖苷类抗生素产生抗药性的主要机制之一是它们被O-核苷酸转移酶（NTases）灭活。林可霉素核苷基转移酶（Lnu）和氨基糖苷核苷基转移酶（ANT）酶的显着序列变异加上缺乏有关这些酶对化学独特的抗生素支架的特异性的分子基础的详细信息，阻碍了遏制这种耐药机制的一般策略的发展。我们进行了广泛的序列分析，确定了129个假定的抗生素NTase，它们构成了Lnu（A），Lnu（B），Lnu（C），Lnu（D），Lnu（F）/（G）和ANT（2“代表的六个不同的亚家族由于以前仅对Lnu（B）酶进行了详细研究，因此我们对Lnu（A）和Lnu（D）酶进行了生物化学表征，其中前者代表了序列最独特的Lnu直系同源物，我们还确定了晶体结构。与林可酰胺复合的Lnu（A）酶的结构。这些数据表明，抗生素NTases组在共享N末端核苷酸转移酶结构域的同时，具有结构不同的C末端结构域（CTD），适合容纳抗生素。其中的抗生素NTase通过活性位点可塑性合理化了其对林可酰胺与氨基糖苷的特异性，从而保留了一般的催化活性，同时接受了由两个域。基于此结构分析，我们建议抗生素NTases根据确定的组从祖先的核苷转移酶沿独立的路径进化而来，其特征在于活性位点的结构变化和结构多样的CTD的募集。这些数据显示了酶驱动的抗生素耐药性的复杂性，并通过确定抗生素NTase的关键统一特征为广泛活性的抑制剂提供了基础。 （C）2015 Elsevier Ltd.保留所有权利。

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