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The zinc transcriptional regulator (ZitR) functions as a metalloregulator that fine tunes transcriptional regulation through zinc-dependent DNA binding. However, the molecular mechanism of zinc-driven allosteric control of the DNA binding to ZitR remains elusive. Here, we performed enhanced sampling accelerated molecular dynamics simulations to figure out the mechanism, revealing the role of protein dynamics in the zinc-induced allosteric control of DNA binding to ZitR. The results suggest that zinc-free ZitR samples distinct conformational states, only a handful of which are compatible with DNA binding. Remarkably, zinc binding reduces the conformational plasticity of the DNA-binding domain of ZitR, promoting the population shift in the ZitR conformational ensemble towards the DNA binding-competent conformation. Further co-binding of DNA to the zinc–ZitR complex stabilizes this competent conformation. These findings suggest that ZitR–DNA interactions are allosterically regulated in a zinc-mediated conformational preselection manner, highlighting the importance of conformational dynamics in the regulation of transcription factor family.

Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR)