Enhancement of RNA/Ligand Association Kinetics via an Electrostatic Anchor
| العنوان: | Enhancement of RNA/Ligand Association Kinetics via an Electrostatic Anchor |
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| المؤلفون: | Daniel Herschlag, Raghuvir N. Sengupta |
| المصدر: | Biochemistry |
| بيانات النشر: | American Chemical Society (ACS), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | inorganic chemicals, Oligoribonucleotides, Guanosine, Molecular Structure, Stereochemistry, Ligand, Chemistry, Oligonucleotide, Static Electricity, RNA, Ligands, Biochemistry, Small molecule, Article, Kinetics, chemistry.chemical_compound, Molecular recognition, Catalytic Domain, Tetrahymena, Nucleic acid, RNA, Catalytic, Literature survey, Protein Binding |
| الوصف: | The diverse biological processes mediated by RNA rest upon its recognition of various ligands, including small molecules and nucleic acids. Nevertheless, a recent literature survey suggests that RNA molecular recognition of these ligands is slow, with association rate constants orders of magnitude below the diffusional limit. Thus, we were prompted to consider strategies for increasing RNA association kinetics. Proteins can accelerate ligand association via electrostatic forces, and here, using the Tetrahymena group I ribozyme, we provide evidence that electrostatic forces can accelerate RNA/ligand association. This RNA enzyme (E) catalyzes cleavage of an oligonucleotide substrate (S) by an exogenous guanosine (G) cofactor. The G 2′- and 3′-OH groups interact with an active site metal ion, termed MC, within E·S·G, and we perturbed each of these contacts via −NH3+ substitution. New and prior data indicate that G(2′NH3+) and G(3′NH3+) bind as strongly as G, suggesting that the −NH3+ substituents of these analogues avoid repulsive interactions with MC and make alternative interactions. Unexpectedly, removal of the adjacent −OH via −H substitution to give G(2′H,3′NH3+) and G(2′NH3+,3′H) enhanced binding, in stark contrast to the deleterious effect of these substitutions on G binding. Pulse–chase experiments indicate that the −NH3+ moiety of G(2′H,3′NH3+) increases the rate of G association. These results suggest that the positively charged −NH3+ group can act as a molecular “anchor” to increase the residence time of the encounter complex and thereby enhance productive binding. Electrostatic anchors may provide a broadly applicable strategy for the development of fast binding RNA ligands and RNA-targeted therapeutics. |
| تدمد: | 1520-4995 0006-2960 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1494ccc590f80f9e506bdba036a0cd3a https://doi.org/10.1021/acs.biochem.9b00231 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....1494ccc590f80f9e506bdba036a0cd3a |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204995 00062960 |
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