Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes.
Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes.
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DOI：
10.1016/j.bbagen.2016.05.040
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Nussinov R
中科院分区：
文献类型：
--
作者：
Ma B;Zhao J;Nussinov R
神经退行性疾病的主要特征是导致神经元损失的蛋白质聚集。使用抗体或抗体片段来靶向聚集体的免疫疗法是一种备受关注的方法。基于淀粉样蛋白的免疫疗法的分子机制是复杂的。破译这些疾病的淀粉样蛋白的特性是必不可少的，以获得深入了解抗体识别的淀粉样抗原。我们系统地探索了与神经退行性疾病相关的抗体-淀粉样蛋白复合物的所有可用晶体结构，包括识别Aβ肽、tau蛋白、朊病毒蛋白、α-突触核蛋白、亨廷顿蛋白（mHTT）和多聚谷氨酰胺的抗体。我们发现抗体主要利用构象选择机制来识别高度柔性的淀粉样蛋白抗原。特别是，solanezumab与Aβ12-28三肽基序构象（F19 F20 A21）结合，这与Aβ42原纤维共有。该基序被抗体捕获，可能提供淀粉样蛋白形成中缺失的环节。水分子通常在抗体和淀粉样蛋白之间架起桥梁，有助于识别。本文为抗体识别淀粉样蛋白提供了结构基础。对已知结构的分析和讨论有望有助于神经退行性疾病中抗体的设计和优化。
The dominant feature in neurodegenerative diseases is protein aggregations that lead to neuronal loss. Immunotherapies using antibodies or antibody fragments to target the aggregations are a highly perused approach. The molecular mechanisms underlying the amyloid-based immunotherapy are complex. Deciphering the properties of amyloidogenic proteins responsible for these diseases is essential to obtain insights into antibody recognition of the amyloid antigens. We systematically explore all available crystal structures of antibody-amyloid complexes related to neurodegenerative diseases, including antibodies that recognize the Aβ peptide, tau protein, prion protein, alpha-synuclein, huntingtin protein (mHTT), and polyglutamine. We found that antibodies mostly use the conformational selection mechanism to recognize the highly flexible amyloid antigens. In particular, solanezumab bound to Aβ12–28 tripeptide motif conformation (F19F20A21), which is shared with the Aβ42 fibril. This motif, which is trapped by the antibody, may provide the missing link in amyloid formation. Water molecules often bridge between the antibody and amyloid, contributing to the recognition. This paper provides the structural basis for antibody recognition of amyloidogenic proteins. The analysis and discussion of known structures are expected to help in the design and optimization of antibodies in neurodegenerative diseases.
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影响因子：
4
作者：
Bohrmann, Bernd;Baumann, Karlheinz;Loetscher, Hansruedi
通讯作者：
Loetscher, Hansruedi
DOI：
10.1073/pnas.0809170106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Antonyuk, S. V.;Trevitt, C. R.;Collinge, J.
通讯作者：
Collinge, J.
影响因子：
2.9
作者：
Hong, Seungpyo;Kim, Dongsup
通讯作者：
Kim, Dongsup
影响因子：
5.6
作者：
Kanyo, ZF;Pan, KM;Cohen, FE
通讯作者：
Cohen, FE
DOI：
10.1107/s0907444912037328
发表时间：
2012-11-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Baral, Pravas Kumar;Wieland, Barbara;James, Michael N. G.
通讯作者：
James, Michael N. G.