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bioRxiv · 10.64898/2026.09.30.755606

Structural mechanism of metal-induced DNA release by an ArsR/SmtB transcriptional regulator

Meireles, D.·Lisboa, J.·Pombinho, R.·Alves, A.·Sousa, S.·Morais-Cabral, J.·Cabanes, D.
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Abstract

Metal-responsive transcriptional regulators must couple metal coordination to DNA release at the DNA-binding interface. However, the pathway connecting these states remains poorly understood. Here, we define this mechanism for the ArsR/SmtB-family repressor CadC from Listeria monocytogenes by combining crystal structures of apo, DNA-bound, and cadmium-bound states with biochemical and in vivo analyses. The DNA-bound structure reveals how CadC dimers bind sequence-specifically to operator DNA, via coordinated major-groove, wing and backbone interactions, with high-affinity binding depending on operator architecture. Cadmium is coordinated at the 3N sensor by an unusual Cys3-Met ligand set and stabilizes a DNA-incompatible conformation through remodeling of DNA-contacting elements and steric incompatibility between the ordered N-terminus and DNA. Mutational analyses show how these structural transitions link to metal-dependent transcriptional control in Listeria cells. We show that CadC binds zinc and supports zinc-responsive transcription in bacterial cells, and that host zinc availability modifies CadC-dependent infection phenotypes. Together, results reveal how metal coordination is converted into DNA release through coupled allosteric remodeling and steric exclusion, establishing a mechanism for signal-dependent transcriptional switching in ArsR/SmtB metalloregulators.

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Meireles, D., Lisboa, J., Pombinho, R., Alves, A., Sousa, S., Morais-Cabral, J., Cabanes, D.. 2026-10-04. Structural mechanism of metal-induced DNA release by an ArsR/SmtB transcriptional regulator. https://doi.org/10.64898/2026.09.30.755606

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