Non-helical DNA Triplex Forms a Unique Aptamer Scaffold for High Affinity Recognition of Nerve Growth Factor
Non-helical DNA Triplex Forms a Unique Aptamer Scaffold for High Affinity Recognition of Nerve Growth Factor
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DOI：
10.1016/j.str.2015.03.027
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发表时间：
2015-07-07
期刊：
影响因子：
5.7
通讯作者：
Janjic, Nebojsa
中科院分区：
文献类型：
--
作者：
Jarvis, Thale C.;Davies, Douglas R.;Janjic, Nebojsa
辨别大分子的结构构件对于理解它们的折叠和功能是必不可少的。对于新一代修饰的核酸配体(称为慢速修饰适体或SOMAmers)，我们以前在众所周知的核酸基序的背景下观察到了疏水性芳香族侧链的基本功能。在这里，我们报道了一个2.45埃分辨率的SOMAmer与神经生长因子络合的晶体结构，它缺乏任何已知的核酸基序，而是采用了类似于三棱柱的构型。SOMAmer利用广泛的疏水堆积相互作用、非正则碱基配对和不规则的嘌呤糖苷键角，采用完全非螺旋的致密S结构。芳香族侧链通过创建前所未有的插层拉链状基序和突出的疏水核心来促进折叠。该结构为SOMAmer的有效抑制活性提供了令人信服的理由，并为SOMAmers特有的结构元件库添加了全新的基序。
Discerning the structural building blocks of macromolecules is essential for understanding their folding and function. For a new generation of modified nucleic acid ligands (called slow off-rate modified aptamers or SOMAmers), we previously observed essential functions of hydrophobic aromatic side chains in the context of well-known nucleic acid motifs. Here we report a 2.45-angstrom resolution crystal structure of a SOMAmer complexed with nerve growth factor that lacks any known nucleic acid motifs, instead adopting a configuration akin to a triangular prism. The SOMAmer utilizes extensive hydrophobic stacking interactions, non-canonical base pairing and irregular purine glycosidic bond angles to adopt a completely non-helical, compact S-shaped structure. Aromatic side chains contribute to folding by creating an unprecedented intercalating zipper-like motif and a prominent hydrophobic core. The structure provides compelling rationale for potent inhibitory activity of the SOMAmer and adds entirely novel motifs to the repertoire of structural elements uniquely available to SOMAmers.