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Potential G-quadruplex sites have been identified in the genomes of DNA and RNA viruses and proposed as regulatory elements. The genus Orthoflavivirus contains arthropod-transmitted, positive-sense, single-stranded RNA viruses that cause significant human disease globally. Computational studies have identified multiple potential G-quadruplex sites that are conserved across members of this genus. Subsequent biophysical studies established that some G-quadruplexes predicted in Zika and tickborne encephalitis virus genomes can form and known quadruplex binders reduced viral yields from cells infected with these viruses. The susceptibility of RNA to degradation and the variability of loop regions have made structure determination challenging. Despite these difficulties,more » we report a high-resolution structure of the NS5-B quadruplex from the West Nile virus genome. Analysis reveals two stacked tetrads that are further stabilized by a stacked triad and transient noncanonical base pairing. This structure expands the landscape of solved RNA quadruplex structures and demonstrates the diversity and complexity of biological quadruplexes. We anticipate that the availability of this structure will assist in solving further viral RNA quadruplexes and provides a model for a conserved antiviral target in Orthoflavivirus genomes.« less

Specific targeting of protein–nucleic acid interactions is an area of current interest, for example, in the regulation of gene-expression. Most transcription factor proteins bind in the DNA major groove; however, we are interested in an approach using small molecules to target the minor groove to control expression by an allosteric mechanism. In an effort to broaden sequence recognition of DNA-targeted-small-molecules to include both A·T and G·C base pairs, we recently discovered that the heterocyclic diamidine, DB2277, forms a strong monomer complex with a DNA sequence containing 5'-AAAGTTT-3'. Competition mass spectrometry and surface plasmon resonance identified new monomer complexes, as wellmore » as unexpected binding of two DB2277 with certain sequences. Inherent microstructural differences within the experimental DNAs were identified through computational analyses to understand the molecular basis for recognition. These findings emphasize the critical nature of the DNA minor groove microstructure for sequence-specific recognition and offer new avenues to design synthetic small molecules for effective regulation of gene-expression.« less