Regulating transcription regulators via allostery and flexibility

Allosteric control of transcriptional regulatory proteins enables organisms to respond to changes in environmental and metabolic conditions. Eukaryotic and prokaryotic transcriptional regulatory proteins sense the availability of a broad range of small molecules including metal ions, metabolites, and drugs with the final biological outcome of altering transcriptional activity of specific genes. This alteration of transcriptional activity is a direct consequence of the ability of the small molecule to elicit a change in the affinity of the transcription factor for its target regulatory site on DNA. Consistent with allosteric mechanisms in general, our understanding of molecular mechanisms by which small-molecule binding perturbs DNA binding by transcriptional regulatory proteins is incomplete. The article by Reichheld et al. (1) in this issue of PNAS provides evidence that the allosteric mechanism in the tetracycline repressor (TetR) is centered on the ability of the small ligand, tetracycline, to alter the folding properties of the repressor protein.