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首页> 外文期刊>Biochemistry >Structures of phage-display peptides that bind to the malarial surface protein, apical membrane antigen 1, and block erythrocyte invasion.
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Structures of phage-display peptides that bind to the malarial surface protein, apical membrane antigen 1, and block erythrocyte invasion.

机译：与疟疾表面蛋白，顶膜抗原1结合并阻止红细胞入侵的噬菌体展示肽的结构。

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摘要

Apical membrane antigen 1 (AMA1) of the human malaria parasite Plasmodium falciparum is synthesized by schizont stage parasites and has been implicated in merozoite invasion of host erythrocytes. Phage-display techniques have recently been used to identify two 15-residue peptides, F1 and F2, which bind specifically to P. falciparum AMA1 and inhibit parasite invasion of erythrocytes [Li, F., et al. (2002) J. Biol. Chem. 277, 50303-50310]. We have synthesized F1, F2, and three peptides with high levels of sequence identity, determined their relative binding affinities for P. falciparum AMA1 with a competition ELISA, and investigated their solution structures by NMR spectroscopy. The strongest binding peptide, F1, contains a beta-turn that includes residues identified via an alanine scan as being critical for binding to AMA1 and inhibition of merozoite invasion of erythrocytes. The three F1 analogues include a 10-residue analogue of F1 truncated at the C-terminus (tF1), a partially scrambled 15-mer (sF1),and a disulfide-constrained 14-mer (F1tbp) which is related to F1 but has a sequence identical to that of a disulfide-constrained loop in the first epidermal growth factor module of the latent transforming growth factor-beta binding protein. tF1 and F1tbp bound competitively with F1 to AMA1, and all three contain a type I beta-turn encompassing key residues involved in F1 binding. In contrast, sF1 lacked this structural motif, and did not compete for binding to AMA1 with F1; rather, sF1 contained a type III beta-turn involving a different part of the sequence. Although F2 was able to bind to AMA1, it was unstructured in solution, consistent with its weak invasion inhibitory effects. Thus, the secondary structure elements observed for these peptides in solution correlate well with their potency in binding to AMA1 and inhibiting merozoite invasion. The structures provide a valuable starting point for the development of peptidomimetics as antimalarial antagonists directed at AMA1.
机译：人疟原虫恶性疟原虫的顶膜抗原1（AMA1）是由裂殖体阶段的寄生虫合成的，并与裂殖子入侵宿主红细胞有关。噬菌体展示技术最近已用于鉴定两个15个残基的肽F1和F2，它们与恶性疟原虫AMA1特异结合并抑制红细胞的寄生虫入侵[Li，F.，等人。 （2002）J.Biol。化学277，50303-50310]。我们已经合成了F1，F2和三个具有高度序列同一性的肽，并通过竞争ELISA确定了它们对恶性疟原虫AMA1的相对结合亲和力，并通过NMR光谱研究了它们的溶液结构。最强的结合肽F1包含一个β转角，其中包含通过丙氨酸扫描鉴定出的与AMA1结合和抑制裂殖子入侵红细胞至关重要的残基。这三个F1类似物包括一个10残基的F1类似物，在C端被截短（tF1），部分加扰的15-mer（sF1）和一个二硫键约束的14-mer（F1tbp），与F1相关，但具有该序列与潜在转化生长因子-β结合蛋白的第一个表皮生长因子模块中的二硫键约束环相同。 tF1和F1tbp与F1与AMA1竞争性结合，并且全部三个都包含I型β-转角，其中包含参与F1结合的关键残基。相反，sF1缺乏该结构基序，并且不与F1竞争与AMA1的结合。而是，sF1包含涉及该序列不同部分的III型β-转角。尽管F2能够与AMA1结合，但它在溶液中是无结构的，与其弱的入侵抑制作用相符。因此，在溶液中观察到的这些肽的二级结构元素与其结合AMA1和抑制裂殖子入侵的能力密切相关。该结构为拟肽作为针对AMA1的抗疟疾拮抗剂的开发提供了有价值的起点。

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