Rapid RNA–ligand interaction analysis through high-information content conformational and stability landscapes

Nathan J. Baird (), James Inglese and Adrian R. Ferré-D’Amaré
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Nathan J. Baird: National Heart, Lung and Blood Institute, NIH
James Inglese: National Center for Advancing Translational Sciences, NIH
Adrian R. Ferré-D’Amaré: National Heart, Lung and Blood Institute, NIH

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract The structure and biological properties of RNAs are a function of changing cellular conditions, but comprehensive, simultaneous investigation of the effect of multiple interacting environmental variables is not easily achieved. We have developed an efficient, high-throughput method to characterize RNA structure and thermodynamic stability as a function of multiplexed solution conditions using Förster resonance energy transfer (FRET). In a single FRET experiment using conventional quantitative PCR instrumentation, 19,400 conditions of MgCl2, ligand and temperature are analysed to generate detailed empirical conformational and stability landscapes of the cyclic diguanylate (c-di-GMP) riboswitch. The method allows rapid comparison of RNA structure modulation by cognate and non-cognate ligands. Landscape analysis reveals that kanamycin B stabilizes a non-native, idiosyncratic conformation of the riboswitch that inhibits c-di-GMP binding. This demonstrates that allosteric control of folding, rather than direct competition with cognate effectors, is a viable approach for pharmacologically targeting riboswitches and other structured RNA molecules.

Date: 2015
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DOI: 10.1038/ncomms9898

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