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首页> 美国卫生研究院文献>Biophysical Journal >The Structural Basis for the Prevention of Nonsteroidal Antiinflammatory Drug-Induced Gastrointestinal Tract Damage by the C-Lobe of Bovine Colostrum Lactoferrin
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The Structural Basis for the Prevention of Nonsteroidal Antiinflammatory Drug-Induced Gastrointestinal Tract Damage by the C-Lobe of Bovine Colostrum Lactoferrin

机译：牛初乳乳铁蛋白的C-Lobe预防非甾体类抗炎药引起的胃肠道损害的结构基础

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Nonsteroidal antiinflammatory drugs (NSAIDs), due to their good efficacy in the treatment of pain, inflammation, and fever, are among the most prescribed class of medicines in the world. The main drawback of NSAIDs is that they induce gastric complications such as peptic ulceration and injury to the intestine. Four NSAIDs, indomethacin, diclofenac, aspirin, and ibuprofen were selected to induce gastropathy in mouse models. It was found that the addition of C-terminal half of bovine lactoferrin (C-lobe) reversed the NSAID-induced injuries to the extent of 47–70% whereas the coadministration of C-lobe prevented it significantly. The C-lobe was prepared proteolytically using serine proteases. The binding studies of C-lobe with NSAIDs showed that these compounds bind to C-lobe with affinities ranging from 2.6 to 4.8 × 10−4 M. The complexes of C-lobe were prepared with the above four NSAIDs. All four complexes were crystallized and their detailed three-dimensional structures were determined using x-ray crystallographic method. The structures showed that all the four NSAID molecules bound to C-lobe at the newly identified ligand binding site in C-lobe that is formed involving two α-helices, α10 and α11. The ligand binding site is separated from the well known iron binding site by the longest and the most stable β-strand, βj, in the structure. Similar results were also obtained with the full length lactoferrin molecule. This novel, to our knowledge, binding site in C-lobe of lactoferrin shows a good complementarity for the acidic and lipophilic compounds such as NSAIDs. We believe this indicates that C-lobe of lactoferrin can be exploited for the prevention of NSAID-induced gastropathy.
机译：非甾体类抗炎药（NSAIDs）由于其在治疗疼痛，炎症和发烧方面的良好功效，是世界上处方最广泛的药物之一。 NSAID的主要缺点是它们会诱发胃部并发症，如消化性溃疡和肠损伤。选择了四种NSAID，消炎痛，双氯芬酸，阿司匹林和布洛芬来诱发小鼠模型的胃病。发现添加牛乳铁蛋白（C瓣）的C端一半可将NSAID诱导的损伤逆转至47％至70％的程度，而同时施用C瓣则可预防这种损伤。使用丝氨酸蛋白酶通过蛋白水解制备C-叶。 C-叶与NSAIDs的结合研究表明，这些化合物以2.6至4.8×10 -4 M的亲和力与C-叶结合。用上述四种方法制备了C-叶的复合物。 NSAID。将所有四个复合物结晶，并使用X射线晶体学方法确定其详细的三维结构。结构表明，所有四个NSAID分子都在新发现的C瓣的配体结合位点与C瓣结合，C瓣由两个α-螺旋α10和α11形成。配体结合位点通过结构中最长和最稳定的β链βj与众所周知的铁结合位点分开。全长乳铁蛋白分子也获得了相似的结果。据我们所知，这本新颖的乳铁蛋白C瓣中的结合位点显示了对酸性和亲脂性化合物（如NSAID）的良好互补性。我们认为这表明乳铁蛋白的C-叶可用于预防NSAID引起的胃病。

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