Structural characterization of native autoinducing peptides and abiotic analogues reveals key features essential for activation and inhibition of an AgrC quorum sensing receptor in Staphylococcus aureus.
Structural characterization of native autoinducing peptides and abiotic analogues reveals key features essential for activation and inhibition of an AgrC quorum sensing receptor in Staphylococcus aureus.
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DOI：
10.1021/ja407533e
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发表时间：
2013-12-11
影响因子：
15
通讯作者：
Blackwell HE
中科院分区：
文献类型：
--
作者：
Tal-Gan Y;Ivancic M;Cornilescu G;Cornilescu CC;Blackwell HE
金黄色葡萄球菌是一种主要的人类病原体，利用群体感应（QS）来控制毒力。其QS系统受大环肽信号（或自动诱导肽（AIPs））及其同源跨膜受体（agcs）的调控。迄今为止，已鉴定出金黄色葡萄球菌的四种不同特异性组（I-IV组），每种组使用不同的AIP:AgrC对。在金黄色葡萄球菌中，能够阻断AIP:AgrC结合的非天然配体和QS作为研究QS途径的化学工具和治疗感染的抗毒策略引起了相当大的兴趣。我们最近报道了一组iii类AIP的类似物，它们能够强烈调节所有四种AgrC受体的活性。对这些配体的进一步发展至关重要的是详细了解对活性至关重要的天然AIPs和非天然类似物的结构特征。在此，我们首次利用核磁共振光谱对已知的天然AIP信号（AIPs-I-IV）和几种具有不同生物活性的AIP- iii类似物进行三维结构分析。将这些核磁共振研究与已知的agc - iii中这些肽的激动作用和拮抗作用相结合，揭示了控制AIP-III（和非天然肽）活性的两个关键结构元件：(1)激活和抑制都必需的三残基疏水“旋环”，以及(2)受体激活所需的外环尾部的第四个锚点。这些结果为aip介导的AgrC在金黄色葡萄球菌中的激活和抑制机制提供了强有力的结构支持，并有助于设计具有增强活性（作为激动剂或拮抗剂）和简化化学结构的新AgrC配体。
Staphylococcus aureus is a major human pathogen that uses quorum sensing (QS) to control virulence. Its QS system is regulated by macrocyclic peptide signals (or autoinducing peptides (AIPs)) and their cognate transmembrane receptors (AgrCs). Four different specificity groups of S. aureus have been identified to date (groups I–IV), each of which uses a different AIP:AgrC pair. Non-native ligands capable of intercepting AIP:AgrC binding, and thereby QS, in S. aureus have attracted considerable interest as chemical tools to study QS pathways and as possible anti-virulence strategies for the treatment of infection. We recently reported a set of analogs of the group-III AIP that are capable of strongly modulating the activity of all four AgrC receptors. Critical to the further development of such ligands is a detailed understanding of the structural features of both native AIPs and non-native analogs that are essential for activity. Herein, we report the first three-dimensional structural analysis of the known native AIP signals (AIPs-I–IV) and several AIP-III analogs with varied biological activities using NMR spectroscopy. Integration of these NMR studies with the known agonism and antagonism profiles of these peptides in AgrC-III revealed two key structural elements that control AIP-III (and non-native peptide) activity: (1) a tri-residue hydrophobic “knob” essential for both activation and inhibition, and (2) a fourth anchor point on the exocyclic tail needed for receptor activation. These results provide strong structural support for a mechanism of AIP-mediated AgrC activation and inhibition in S. aureus, and should facilitate the design of new AgrC ligands with enhanced activities (as agonists or antagonists) and simplified chemical structures.
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影响因子：
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