The original view of our DNA as a relatively static B-form double helix has been disrupted by studies finding, for example, that the bases frequently and transiently adopt Hoogsteen base-pairing. Raluca Gordân and colleagues have now quantified the energetic cost of transcription factor–DNA binding, and find that mismatches within the binding site can actually lower this cost. These data show that the readout of the DNA sequence is not the only factor used by transcription factors when they are binding to DNA, but that the energetic penalty is also taken into account.
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