NiaR is a regulatory protein that represses the expression of proteins involved in the de novo biosynthesis and uptake of nicotinic acid (NA), with NA acting as a co-repressor. The previously published structure of NiaR from Thermotoga maritima (TmNiaR) identified it as a functional homodimer containing a transition metal ion in a suspected NA-binding pocket. Here, we present the crystal structure of NA bound to the iron-metalated form of TmNiaR. Supported by spectroscopic and solution studies, this structure shows that NA binds to a protein-bound ferrous ion via its ring nitrogen. In addition, the carboxylate group on NA interacts with Tyr108 from the dyad-related subunit, repositioning the likely DNA-binding domains of the dimer to promote high-affinity interactions with DNA operators. The specificity of TmNiaR for NA can be explained by the hydrogen bonding scheme within the NA-binding pocket.
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