A transition state analogue for an RNA-editing reaction

Journal of the American Chemical Society
Brittany L HaudenschildPeter A Beal

Abstract

Deamination at C6 of adenosine in RNA catalyzed by the ADAR enzymes generates inosine at the corresponding position. Because inosine is decoded as guanosine during translation, this modification can lead to codon changes in messenger RNA. Hydration of 8-azanebularine across the C6-N1 double bond generates an excellent mimic of the transition state proposed for the hydrolytic deamination reaction catalyzed by ADARs. Here, we report the synthesis of a phosphoramidite of 8-azanebularine and its use in the preparation of RNAs mimicking the secondary structure found at a known editing site in the glutamate receptor B subunit pre-mRNA. The binding properties of analogue-containing RNAs indicate that a tight binding ligand for an ADAR can be generated by incorporation of 8-azanebularine. The observed high-affinity binding is dependent on a functional active site, the presence of one, but not the other, of ADAR2's two double-stranded RNA-binding motifs (dsRBMs), and the correct placement of the nucleoside analogue into the sequence/structural context of a known editing site. These results advance our understanding of substrate recognition during ADAR-catalyzed RNA editing and are important for structural studies of ADAR.RNA complexes.

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Citations

Dec 14, 2011·ACS Chemical Biology·Kelly PhelpsPeter A Beal
Aug 1, 2009·Journal of the American Chemical Society·Subhash PokharelPeter A Beal
Aug 11, 2006·Organic Letters·Olena Maydanovych, Peter A Beal
Apr 12, 2016·Nature Structural & Molecular Biology·Melissa M MatthewsPeter A Beal
Jan 8, 2015·Nucleic Acids Research·Kelly J PhelpsPeter A Beal
Dec 13, 2016·RNA Biology·Andrew J Fisher, Peter A Beal
Jan 13, 2005·Chembiochem : a European Journal of Chemical Biology·Peter A Beal
Jul 2, 2009·Journal of Computational Chemistry·Selina C WangDean J Tantillo
Jan 31, 2020·The Journal of Biological Chemistry·Michael L Hayes, Paola I Santibanez
Feb 22, 2017·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Justin M Thomas, Peter A Beal
Feb 10, 2017·Nucleic Acids Research·Elizabeth A Jolley, Brent M Znosko
Aug 1, 2020·Science·Audrone LapinaiteJennifer A Doudna
Jul 1, 2020·Nucleic Acids Research·Alexander S Thuy-BounPeter A Beal
Dec 26, 2018·Cell Chemical Biology·Leanna R MonteleonePeter A Beal
Aug 10, 2006·Chemical Reviews·Olena Maydanovych, Peter A Beal
May 4, 2021·Journal of the American Chemical Society·Erin E DohertyPeter A Beal

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