Evolution of abiotic cubane chemistries in a nucleic acid aptamer allows selective recognition of a malaria biomarker
Evolution of abiotic cubane chemistries in a nucleic acid aptamer allows selective recognition of a malaria biomarker
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DOI：
10.1073/pnas.2003267117
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发表时间：
2020-07-21
影响因子：
11.1
通讯作者：
Tanner, Julian A.
中科院分区：
文献类型：
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作者：
Cheung, Yee-Wai;Rothlisberger, Pascal;Tanner, Julian A.
通过系统进化配体指数富集法(SELEX)选择的核酸适配子折叠成精致的球状结构，与具有不同翻译应用的蛋白质靶标形成复合体。改变核苷酸的化学成分允许非自然核酸的进化，但外来化学物质可以在多大程度上整合到SELEX选择中以进化非自然大分子结合界面尚不清楚。在这里，我们报告了一种立方烷修饰的适体(Cuamer)对疟疾生物标记物间日疟原虫乳酸脱氢酶(PvLDH)的识别。该配合物的晶体结构揭示了一种前所未有的结合机制，涉及到疏水口袋中的多立方烷簇合物。通过立方氢的氢键进一步稳定了结合作用，这在以前的大分子结合界面中是没有观察到的。这种结合机制允许间日疟原虫对恶性疟原虫乳酸脱氢酶的歧视性识别，从而区分这些高度保守的疟疾生物标志物用于诊断应用。综上所述，我们的数据表明，SELEX可以用于进化具有化学功能基团的外来核酸，这些基团能够实现生物学上从未观察到的显著结合机制。延伸到其他奇异的化学领域将为功能核酸打开无数的可能性。
Nucleic acid aptamers selected through systematic evolution of ligands by exponential enrichment (SELEX) fold into exquisite globular structures in complex with protein targets with diverse translational applications. Varying the chemistry of nucleotides allows evolution of nonnatural nucleic acids, but the extent to which exotic chemistries can be integrated into a SELEX selection to evolve nonnatural macromolecular binding interfaces is unclear. Here, we report the identification of a cubane-modified aptamer (cubamer) against the malaria biomarker Plasmodium vivax lactate dehydrogenase (PvLDH). The crystal structure of the complex reveals an unprecedented binding mechanism involving a multicubane cluster within a hydrophobic pocket. The binding interaction is further stabilized through hydrogen bonding via cubyl hydrogens, previously unobserved in macromolecular binding interfaces. This binding mechanism allows discriminatory recognition of P. vivax over Plasmodium falciparum lactate dehydrogenase, thereby distinguishing these highly conserved malaria biomarkers for diagnostic applications. Together, our data demonstrate that SELEX can be used to evolve exotic nucleic acids bearing chemical functional groups which enable remarkable binding mechanisms which have never been observed in biology. Extending to other exotic chemistries will open a myriad of possibilities for functional nucleic acids.