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Biol."],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Sequence\u2010specific binding by transcription factors (TFs) plays a significant role in the selection and regulation of target genes. At the protein:DNA interface, amino acid side\u2010chains construct a diverse physicochemical network of specific and non\u2010specific interactions, and seemingly subtle changes in amino acid identity at certain positions may dramatically impact TF:DNA binding. Variation of these specificity\u2010determining residues (SDRs) is a major mechanism of functional divergence between TFs with strong structural or sequence homology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we employed a combination of high\u2010throughput specificity profiling by SELEX and Spec\u2010seq, structural modeling, and evolutionary analysis to probe the binding preferences of winged helix\u2010turn\u2010helix TFs belonging to the OmpR sub\u2010family in <jats:italic>Escherichia coli<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that <jats:italic>E. coli<\/jats:italic> OmpR paralogs recognize tandem, variably spaced repeats composed of \u201cGT\u2010A\u201d or \u201cGCT\u201d\u2010containing half\u2010sites. Some divergent sequence preferences observed within the \u201cGT\u2010A\u201d mode correlate with amino acid similarity; conversely, \u201cGCT\u201d\u2010based motifs were observed for a subset of paralogs with low sequence homology. Direct specificity profiling of a subset of OmpR homologues (CpxR, RstA, and OmpR) as well as predicted \u201cSDR\u2010swap\u201d variants revealed that individual SDRs may impact sequence preferences locally through direct contact with DNA bases or distally via the DNA backbone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Overall, our work provides evidence for a common structural \u201ccode\u201d for sequence\u2010specific wHTH\u2010DNA interactions, and demonstrates that surprisingly modest residue changes can enable recognition of highly divergent sequence motifs. Further examination of SDR predictions will likely reveal additional mechanisms controlling the evolutionary divergence of this important class of transcriptional regulators.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s40484-018-0130-0","type":"journal-article","created":{"date-parts":[[2018,2,13]],"date-time":"2018-02-13T06:11:03Z","timestamp":1518502263000},"page":"68-84","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Deciphering the protein\u2010DNA code of bacterial winged helix\u2010turn\u2010helix transcription factors"],"prefix":"10.1002","volume":"6","author":[{"given":"Adam P.","family":"Joyce","sequence":"first","affiliation":[{"name":"<!--1--> Program in Developmental, Regenerative, and Stem Cell Biology Washington University in St. Louis St. Louis MO 63110 USA"}]},{"given":"James J.","family":"Havranek","sequence":"additional","affiliation":[{"name":"<!--2--> Department of Biochemistry and 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