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首页> 外文期刊>Journal of Molecular Biology >Amyloid-beta-anti-amyloid-beta complex structure reveals an extended in the immunodominant conformation B-Cell epitope
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Amyloid-beta-anti-amyloid-beta complex structure reveals an extended in the immunodominant conformation B-Cell epitope

机译：淀粉样蛋白-抗淀粉样蛋白-β复合物结构揭示了在免疫显性构象B细胞表位中的延伸

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摘要

Alzheimer's disease (AD) is the most common form of dementia. Amyloid-beta (A beta) peptide, generated by proteolytic cleavage of the amyloid precursor protein, is central to AD pathogenesis. Most pharmaceutical activity in AD research has focused on A beta, its generation and clearance from the brain. In particular, there is much interest in immunotherapy approaches with a number of anti-A beta antibodies in clinical trials. We have developed a monoclonal antibody, called WO2, which recognises the A beta pepti this end, we have determined the three-dimensional structure, to near atomic resolution, of both the antibody and the complex with its antigen, the A peptide. The structures reveal the molecular basis for WO2 recognition and binding of A. The A peptide adopts an extended, coil-like conformation across its major immunodominant B-cell epitope between residues 2 and 8. We have also studied the antibody-bound A beta peptide in the presence of metals known to affect its aggregation state and show that WO2 inhibits these interactions. Thus, antibodies that target the N-terminal region of A beta, such as WO2, hold promise for therapeutic development. (c) 2007 Elsevier Ltd. All rights reserved.
机译：阿尔茨海默氏病（AD）是痴呆症的最常见形式。通过淀粉样蛋白前体蛋白的蛋白水解切割产生的淀粉样蛋白β（A beta）肽是AD发病机制的关键。 AD研究中的大多数药物活性都集中在A beta，它的产生和从大脑清除。尤其是，在临床试验中，人们对使用多种抗Aβ抗体的免疫治疗方法非常感兴趣。我们已经开发出一种名为WO2的单克隆抗体，该抗体可以识别Aβ肽，为此，我们已经确定了该抗体及其复合物及其抗原A肽的三维结构，接近原子分辨率。该结构揭示了WO2识别和结合A的分子基础。A肽在残基2和8之间跨越其主要的主要免疫B细胞表位采用了扩展的，盘绕状构象。我们还研究了与抗体结合的Aβ肽在已知会影响其聚集状态并显示WO2抑制这些相互作用的金属存在下。因此，靶向Aβ的N末端区域的抗体，例如WO2，有望用于治疗。 （c）2007 Elsevier Ltd.保留所有权利。

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