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首页> 外文期刊>Journal of Molecular Biology >Crystal structure of an anti-meningococcal subtype P1.4 PorA antibody provides basis for peptide-vaccine design
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Crystal structure of an anti-meningococcal subtype P1.4 PorA antibody provides basis for peptide-vaccine design

机译：抗脑膜炎球菌亚型P1.4 PorA抗体的晶体结构为肽疫苗设计提供了基础

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摘要

In various western countries, subtype P1.4 of Neisseria meningitidis serogroup B causes the greatest incidence of meningococcal disease. To investigate the molecular recognition of this subtype, we crystallised a peptide ((P1)HVVVNNKVATH(P11)), corresponding to the subtype P1.4 epitope sequence of outer membrane protein PorA, in complex with a Fab fragment of the bactericidal antibody MN20B9.34 directed against this epitope. Structure determination at 1.95 angstrom resolution revealed a unique complex of one P1.4 antigen peptide bound to two identical Fab fragments. One Fab recognises, the putative epitope residues in a 2:2 type I beta-turn at residues (NNKVP8)-N-P5, whereas the other Fab binds the C-terminal residues of the peptide that we consider a crystallisation artefact. Interestingly, recognition of the P1.4 epitope peptide is mediated almost exclusively through the complementarity-determining regions of the heavy chain. We exploited the observed turn conformation for designing conformationally restricted cyclic peptides for use as a peptide vaccine. The conformational stability of the two peptide designs was assessed by molecular dynamics simulations. Unlike the linear peptide, both cyclic peptides, conjugated to tetanus toxoid as a carrier protein, elicited antibody responses in mice that recognised meningococci of subtype P1.7-2,4. Serum bactericidal assays showed that some, but not all, of the sera induced with the cyclic peptide conjugates could activate the complement system with titres that were very high compared to the titres induced by complete PorA protein in its native conformation administered in outer membrane vesicles. (c) 2005 Elsevier Ltd. All rights reserved.
机译：在西方许多国家，脑膜炎奈瑟氏菌血清群B的P1.4亚型引起脑膜炎球菌疾病的发病率最高。为了研究该亚型的分子识别，我们将与外膜蛋白PorA的亚型P1.4表位序列相对应的肽（（P1）HVVVNNKVATH（P11））与杀菌抗体MN20B9的Fab片段复合形成了结晶。 34针对该表位。在1.95埃分辨率下的结构测定揭示了一个P1.4抗原肽与两个相同Fab片段结合的独特复合物。一个Fab识别出，在残基（NNKVP8）-N-P5处，I型β转为2：2的假定表位残基，而另一个Fab结合了我们认为是结晶伪像的肽的C端残基。有趣的是，P1.4表位肽的识别几乎仅通过重链的决定互补性的区域介导。我们利用观察到的转弯构象来设计用作肽疫苗的构象受限的环肽。通过分子动力学模拟评估了两种肽设计的构象稳定性。与线性肽不同，两种环状肽都与破伤风类毒素作为载体蛋白偶联，在识别P1.7-2,4亚型脑膜炎球菌的小鼠中引起抗体应答。血清杀菌试验显示，与环状多肽结合物诱导的血清滴度相比，由完整肽诱导的效价非常高，而环肽结合物诱导的部分（而非全部）血清可以激活补体系统。 （c）2005 Elsevier Ltd.保留所有权利。

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