Streptococcus pneumoniae is a Gram-positive, facultative anaerobic bacteria that colonizes in the upper respiratory tract of most humans. Pathogens like S. pneumoniae rely on their host to provide all nutrients for growth, which includes several transition metal ions. Zinc(II) ions are required micronutrients for all living systems. The intracellular Zn2+ concentration in S. pneumoniae is regulated by two transcription factors (TFs). These proteins, termed AdcR and SczA, are known to bind Zn2+ ions with high affinity. In both proteins, the zinc(II) binding events induce a structural change in the protein that affords a dramatic increase in the affinity of these Zn-TFs for their specific DNA promotor regions. It is this process that regulates a series of proteins responsible for Zn2+ homeostasis within S. pneumoniae. The chemical equilibria between Zn2+, TFs, and DNA are attractive targets for therapeutic agent development, where impacting S. pneumoniae’s ability to adapt to new locations within a host can directly impact its virulence. AdcR binds two Zn2+ ions in its metal binding domain, and this binding site is stabilized through a series of intramolecular interactions between an unstructured loop in the protein. Specifically, site 1 is a coordinatively saturated tetrahedral site, where all four positions are coordinated through amino-acid side chain residues. Site 2 also adopts a tetrahedral coordination mode, however one of these sites is occupied by a water molecule, which provides an opportunity to disrupt this system. The central hypothesis associated with this proposal is that zinc(II) binding induces an organization of a dynamic loop in AdcR (Lys22 to Ser38), which locks the protein into a favorable DNA binding conformation. Perturbations to the structure of this loop by mutation (aim 1) or chemical agents (aim 2) can impact the Zn2AdcR structure significantly leading to changes in the thermodynamics of Zn2AdcR/DNA binding.