Research
We work on clinically and biophysically important protein families with interesting sub-specializations.
We use bioinformatic, biochemical, and structural techniques to figure out how different sub-families of proteins set themselves apart from each other.
As a lab, all of our projects ask how enzymes are tuned by evolution for divergent tasks. Those tasks may be existing at high temperature, recognizing a unique substrate, or engaging in ionic interactions in high-salinity solutions. We're curious about how changes at the amino acid level support these differential specializations.​
Many of our projects are collaborative. There are some key systems we focus on in the lab, but we're always interested in finding protein classes with interesting features that can help us ask unique questions about how sequence, structure, and function are linked.
Extremophilic specialization in DNA topoisomerases
DNA topoisomerases are enzymes that manage DNA topology, the specific types of twist and writhe that every DNA molecule adopts. Topoisomerases are a diverse and mechanistically complex family of proteins essential to all forms of life, which has lead to their development as chemotherapeutic and antibacterial targets. Environmental factors such as temperature and growth rate affect topological homeostasis, and topoisomerases have evolved to address these diverse niches.
We're interested in how topoisomerases have evolved to manage the genome topology of organisms living in extreme environments. Though they are predicted to be quite similar in overall structure, topoisomerases from psychrophilic (cold-dwelling) and thermophilic (hot-dwelling) organisms must meet very different topological demands. By studying how evolution has solved these unique problems, we can learn more about how enzymes can be both active and stable in extreme temperatures, principles with bearing on bioengineering and protein folding.
Funding: Louisiana Board of Regents Research Competitiveness Subprogram award 081A-20.
Substrate specificity in rRNA methyltransferases
Antibiotic resistance is one of the greatest challenges of modern medicine. As pathogens develop resistance to existing therapies, we must either develop new drugs with new modes of action, or rescue those that have engendered widespread resistance.
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Resistance to the macrolide antibiotics can be conferred by Erm--erythromycin resistance methyltransferase. This enzyme modifies bacterial rRNA at a specific adenine site, preventing drug binding. Understanding how Erm interacts with it's macromolecular target could help the effort to design specific inhibitors that disrupt the action of Erm without affecting the work of housekeeping methyltransferases. Unfortunately, high resolution structural information describing the Erm:RNA complex does not exist.
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The Schoeffler Lab is using bioinformatic and biochemical analyses to uncover the specific determinants of specificity in the Erm family. This project is a collaboration with the Dunkle group at UA Tuscaloosa. Funding: NIH-AREA
Psychrohalophilicity in DNA Polymerase I
If there's life on other planets, there's a good chance that it's (1) microbial and (2) existing in an extreme environment, like the cold, salty, sub-surface ocean of Jupiter's moon Europa. How might life exist--or even thrive--in these harsh conditions?
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We're using structural biology and bioinformatics to investigate how one of the most critical biochemical processes underlying life on Earth--DNA replication--might take place in a psychrohalophilic environment like Europa. How do the ionic interactions that underly many protein:DNA binding interactions persist in presence of high ionic strength solutions? How do the dynamics that are necessary for catalysis take place despite the rigidifying effects of cold? We're investigating this question as part of a collaborative project with the LiCata Lab at Louisiana State University. Funding: NASA
Distributions of glycines near the DNA binding site of the Pol 1 polymerase domain in psychrophilic (blue), halophilic (green) and thermophilic (pink) homologs. (Histograms by Larissa Cortes Morales)