# Zinc dependent conformational changes in AdcR and their impact on DNA binding

> **NIH NIH P20** · MISSISSIPPI STATE UNIVERSITY · 2021 · $308,882

## Abstract

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.

## Key facts

- **NIH application ID:** 10469718
- **Project number:** 5P20GM103646-09
- **Recipient organization:** MISSISSIPPI STATE UNIVERSITY
- **Principal Investigator:** Joseph P Emerson
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $308,882
- **Award type:** 5
- **Project period:** 2021-04-29 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469718

## Citation

> US National Institutes of Health, RePORTER application 10469718, Zinc dependent conformational changes in AdcR and their impact on DNA binding (5P20GM103646-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10469718. Licensed CC0.

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