Evoking picomolar binding in RNA by a single phosphorodithioate linkage.
Evoking picomolar binding in RNA by a single phosphorodithioate linkage.
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DOI：
10.1093/nar/gkw725
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发表时间：
2016-09-30
影响因子：
14.9
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Abeydeera ND;Egli M;Cox N;Mercier K;Conde JN;Pallan PS;Mizurini DM;Sierant M;Hibti FE;Hassell T;Wang T;Liu FW;Liu HM;Martinez C;Sood AK;Lybrand TP;Frydman C;Monteiro RQ;Gomer RH;Nawrot B;Yang X
RNA适配子是人工合成的基于寡核苷酸的亲和分子，利用独特的三维结构对蛋白质等靶标进行亲和力和特异性。与生物产生的抗体相比，它们具有许多优点；然而，RNA适配子的结合亲和力和特异性往往不足以成功地应用于诊断分析或作为治疗剂。强大的结合亲和力对于改善下游应用非常重要。我们在这里报告了使用在RNA适配子的单核苷酸上的磷酸二硫代酸(PS2)取代来显著提高靶结合亲和力的∼1000倍(从纳摩尔到皮摩尔)。α-凝血酶：PS2-适配子复合体的X射线共晶结构表明，含有PS2的核苷酸发生了局部的诱导FIT重排，从而导致了增强的靶向相互作用。对模拟PS2部分和苯丙氨酸的模型体系的高水平量子力学计算表明，硫和芳香环之间的边向相互作用是非常有利的，也证实了硫类似物比相应的磷酸盐更容易极化。这种涉及硫原子的有利相互作用在完整的适体-蛋白质复合体中可能比在模型体系中更显着。
RNA aptamers are synthetic oligonucleotide-based affinity molecules that utilize unique three-dimensional structures for their affinity and specificity to a target such as a protein. They hold the promise of numerous advantages over biologically produced antibodies; however, the binding affinity and specificity of RNA aptamers are often insufficient for successful implementation in diagnostic assays or as therapeutic agents. Strong binding affinity is important to improve the downstream applications. We report here the use of the phosphorodithioate (PS2) substitution on a single nucleotide of RNA aptamers to dramatically improve target binding affinity by ∼1000-fold (from nanomolar to picomolar). An X-ray co-crystal structure of the α-thrombin:PS2-aptamer complex reveals a localized induced-fit rearrangement of the PS2-containing nucleotide which leads to enhanced target interaction. High-level quantum mechanical calculations for model systems that mimic the PS2 moiety and phenylalanine demonstrate that an edge-on interaction between sulfur and the aromatic ring is quite favorable, and also confirm that the sulfur analogs are much more polarizable than the corresponding phosphates. This favorable interaction involving the sulfur atom is likely even more significant in the full aptamer-protein complexes than in the model systems.
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影响因子：
3.7
作者：
Gold L;Ayers D;Bertino J;Bock C;Bock A;Brody EN;Carter J;Dalby AB;Eaton BE;Fitzwater T;Flather D;Forbes A;Foreman T;Fowler C;Gawande B;Goss M;Gunn M;Gupta S;Halladay D;Heil J;Heilig J;Hicke B;Husar G;Janjic N;Jarvis T;Jennings S;Katilius E;Keeney TR;Kim N;Koch TH;Kraemer S;Kroiss L;Le N;Levine D;Lindsey W;Lollo B;Mayfield W;Mehan M;Mehler R;Nelson SK;Nelson M;Nieuwlandt D;Nikrad M;Ochsner U;Ostroff RM;Otis M;Parker T;Pietrasiewicz S;Resnicow DI;Rohloff J;Sanders G;Sattin S;Schneider D;Singer B;Stanton M;Sterkel A;Stewart A;Stratford S;Vaught JD;Vrkljan M;Walker JJ;Watrobka M;Waugh S;Weiss A;Wilcox SK;Wolfson A;Wolk SK;Zhang C;Zichi D
通讯作者：
Zichi D
影响因子：
2.9
作者：
Alkorta, Ibon;Sanchez-Sanz, Goar;Del Bene, Janet E.
通讯作者：
Del Bene, Janet E.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1038/nsb0298-133
发表时间：
1998-02-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Convery, MA;Rowsell, S;Stockley, PG
通讯作者：
Stockley, PG
影响因子：
4.1
作者：
Fukaya, Takahiro;Abe, Koichi;Ikebukuro, Kazunori
通讯作者：
Ikebukuro, Kazunori