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Transcriptional regulation is crucial for all biological processes and well investigated at the molecular level for a wide range of organisms. However, it is quite unclear how innovations, such as the activity of a novel regulatory element, evolve. In the case of transcription factor (TF) binding, both a novel TF and a novel-binding site would need to evolve concertedly. Since promiscuous functions have recently been identified as important intermediate steps in creating novel specific functions in many areas such as enzyme evolution and protein–protein interactions, we ask here how promiscuous binding of TFs to TF-binding sites (TFBSs) affects the robustness and evolvability of this tightly regulated system. Specifically, we investigate the binding behavior of several hundred TFs from different species at unprecedented breadth. Our results illustrate multiple aspects of TF-binding interactions, ranging from correlations between the strength of the interaction bond and specificity, to preferences regarding TFBS nucleotide composition in relation to both domains and binding specificity. We identified a subset of high A/T binding motifs. Motifs in this subset had many functionally neutral one-error mutants, and were bound by multiple different binding domains. Our results indicate that, especially for some TF–TFBS associations, low binding specificity confers high degrees of evolvability, that is that few mutations facilitate rapid changes in transcriptional regulation, in particular for large and old TF families. In this study we identify binding motifs exhibiting behavior indicating high evolutionary potential for innovations in transcriptional regulation. [ABSTRACT FROM AUTHOR]