Crystal structures of a quorum-quenching antibody
Crystal structures of a quorum-quenching antibody
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DOI：
10.1016/j.jmb.2007.02.081
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发表时间：
2007-05-18
影响因子：
5.6
通讯作者：
Wilson, Ian A.
中科院分区：
文献类型：
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作者：
Debler, Erik W.;Kaufmann, Gunnar F.;Wilson, Ian A.
大量革兰氏阴性菌以n -酰基高丝氨酸内酯（N-acyl homoserine lactones, AHLs）作为群体感应信号分子，通过群体密度依赖性机制协调基因表达。RS2-1G9抗体是针对n -酰基高丝氨酸内酯的内酰胺类模拟物诱导的，是唯一报道的识别天然存在的高亲和力n -酰基高丝氨酸内酯的单克隆抗体。RS2-1G9具有较高的交叉反应性，对铜绿假单胞菌（Pseudomonas aeruginosa）的群体感应信号有明显的抑制作用。Fab RS2-lG9与内酰胺配合物的晶体结构。模拟结果显示，在抗体结合位点，极性内酰胺部分被完全包裹。这种识别模式提供了一种优雅的免疫解决方案，可以与脂肪族紧密结合，类脂体配体具有小的头基，缺乏典型的半抗原特征，如芳香性或电荷，这些特征通常被纳入半抗原设计以产生高亲和力抗体。RS2-lG9区分密切相关ahl的能力是由配体上的6个氢键赋予的。相反，RS2-1G9对内酯的交叉反应性可能源于这些氢键的守恒以及内酯环氧的额外氢键。在蛋白质表面有一个短而窄的通道，容纳了一部分酰基链，不允许头部基团进入。没有同源内酰胺或内酯配体的抗体的晶体结构显示了一个明显改变的抗体结合位点和一个封闭的结合口袋。奇怪的是，一个完全埋藏的乙二醇分子模仿内酰胺环，从而充当替代配体。这种群体猝灭抗体的详细结构描述将有助于进一步开发一种基于抗体的治疗方法，通过干扰群体感应来对抗细菌病原体。(C) 2007 Elsevier Ltd.版权所有。
A large number of Gram-negative bacteria employ N-acyl homoserine lactones (AHLs) as signaling molecules in quorum sensing, which is a population density-dependent mechanism to coordinate gene expression. Antibody RS2-1G9 was elicited against a lactam mimetic of the N-acyl homoserine lactone and represents the only reported monoclonal antibody that recognizes the naturally-occuring N-acyl homoserine lactone with high and affinity. Due to its high cross-reactivity, RS2-1G9 showed remarkable inhibition of quorum sensing signaling in Pseudomonas aeruginosa, a common opportunistic pathogen in humans. The crystal structure of Fab RS2-lG9 in complex with a lactam. analog revealed complete encapsulation of the polar lactam moiety in the antibody-combining site. This mode of recognition provides an elegant immunological solution for tight binding to an aliphatic, hpid-like ligand with a small head group lacking typical haptenic features, such as aromaticity or charge, which are often incorporated into hapten design to generate high-affinity antibodies. The ability of RS2-lG9 to discriminate between closely related AHLs is conferred by six hydrogen bonds to the ligand. Conversely, cross-reactivity of RS2-1G9 towards the lactone is likely to originate from conservation of these hydrogen bonds as well as an additional hydrogen bond to the oxygen of the lactone ring. A short, narrow tunnel exiting at the protein surface harbors a portion of the acyl chain and would not allow entry of the head group. The crystal structure of the antibody without its cognate lactam or lactone ligands revealed a considerably altered antibody-combining site with a closed binding pocket. Curiously, a completely buried ethylene glycol molecule mintics the lactam ring and, thus, serves as a surrogate ligand. The detailed structural delineation of this quorum-quenching antibody will aid further development of an antibody-based therapy against bacterial pathogens by interference with quorum sensing. (C) 2007 Elsevier Ltd. All rights reserved.