Evoking picomolar binding in RNA by a single phosphorodithioate linkage

被引:92
作者
Abeydeera, N. Dinuka [1 ]
Egli, Martin [2 ]
Cox, Nehemiah [3 ]
Mercier, Karen [4 ]
Conde, Jonas Nascimento [5 ]
Pallan, Pradeep S. [2 ]
Mizurini, Daniella M. [6 ]
Sierant, Malgorzata [7 ]
Hibti, Fatima-Ezzahra [4 ]
Hassell, Tom [8 ]
Wang, Tianzhi [9 ]
Liu, Feng-Wu [10 ]
Liu, Hong-Min [10 ]
Martinez, Carlos [8 ]
Sood, Anil K. [11 ,12 ,13 ]
Lybrand, Terry P. [14 ,15 ,16 ]
Frydman, Chiraz [4 ]
Monteiro, Robson Q. [6 ]
Gomer, Richard H. [3 ]
Nawrot, Barbara [7 ]
Yang, Xianbin [1 ]
机构
[1] AM Biotechnol LLC, 12521 Gulf Freeway, Houston, TX 77034 USA
[2] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA
[3] Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA
[4] Horiba Sci, Biointeract Div, Ave Vauve Passage JobinYvon,CS 45002, Palaiseau, France
[5] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941 Rio De Janeiro, RJ, Brazil
[6] Univ Fed Rio de Janeiro, Inst Bioquim Med Leopoldo de Meis, BR-21941 Rio De Janeiro, RJ, Brazil
[7] Polish Acad Sci, Ctr Mol & Macromol Studies, Dept Bioorgan Chem, Sienkiewicza 112, PL-90363 Lodz, Poland
[8] MilliporeSigma, 9186 Six Pines, The Woodlands, TX 77380 USA
[9] Univ Texas Med Branch, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA
[10] Zhengzhou Univ, Sch Pharmaceut Sci, Sci Ave 100, Zhengzhou 450001, Henan, Peoples R China
[11] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77054 USA
[12] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77054 USA
[13] Univ Texas MD Anderson Canc Ctr, Ctr RNAi & Noncoding RNA, Houston, TX 77054 USA
[14] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA
[15] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA
[16] Vanderbilt Univ, Struct Biol Ctr, Nashville, TN 37232 USA
基金
美国国家卫生研究院;
关键词
IN-VITRO SELECTION; CRYSTAL-STRUCTURE; MOLECULAR RECOGNITION; DNA APTAMERS; PROTEIN; AFFINITY; COMPLEX; STEREOCHEMISTRY; GENERATION; LIGANDS;
D O I
10.1093/nar/gkw725
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 similar to 1000-fold (from nanomolar to picomolar). An X-ray co-crystal structure of the alpha-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.
引用
收藏
页码:8052 / 8064
页数:13
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