Overview

Our laboratory investigates the structural basis for recognition, biochemical function and biological specificity of proteins and nucleic acids. Specifically, we study systems involved in bacterial pathogenesis, cell signaling, and cancer at the molecular level. Rather than focusing on specific techniques, we take a problem-oriented approach and use whichever techniques are necessary to answer the question at hand. Often, this requires complementary application of structural approaches including spectroscopy, scattering, crystallography and microscopy. We also prioritize tight coupling of our research to functional analysis. This strategy is by nature very collaborative and collegial, and has stimulated involvement in many multi-investigator projects. The following lists key questions that we are addressing, including links to papers that provide an overview of the specific research projects. You can find a complete list of our publications here.

Key questions:

1. What is the mechanism of action of the multi-protein nuclear excision repair (NER) machinery and the basis for mal-function caused by disease-associated mutations? Is suppression of the DNA damage response, or NER alone, a viable strategy to enhance the efficacy of anti-cancer therapeutics?
   • (2016) XPA: a key scaffold for human nucleotide excision repair. DNA Repair.
   • (2014) Redefining the DNA-binding domain of human XPA. Journal of the American Chemical Society.

2. How is the gene duplication phase of DNA replication initiated? How do replicative polymerases communicate?
   • (2017) The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport. Science.
   • (2010) Insights into eukaryotic DNA priming from the structure and functional interactions of the 4Fe-4S cluster domain of human DNA primase. Proceedings of the National Academy of Sciences USA.
3. What are the mechanisms of action of calprotectin in the innate immune response to host infection by pathogens? What are the means by which microorganisms pirate essential trace metals from calprotectin?
   • (2013) Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens. Proceedings of the National Academy of Sciences USA.
   •  (2008) Metal chelation and inhibition of bacterial growth in tissue abscesses. Science.

3. How do S100 proteins activate the receptor for advanced glycation end products (RAGE)? Is inhibition of RAGE-ligand interactions a viable strategy to suppress the chronic inflammation symptoms of diabetics?
   • (2010) Structural basis for ligand recognition and activation of RAGE. Structure.
   • (2007) The extracellular region of the receptor for advanced glycation end products is composed of two independent structural units. Biochemistry.

5. How does intracellular calcium signaling regulate cardiac ion channels? How do mutations affecting the calcium sensing apparatus in cardiac ion channels and in calmodulin cause cardiac arrhythmia syndromes?
   • (2006) Calcium-dependent regulation of the voltage-gated sodium channel hH1: Intrinsic and extrinsic sensors use a common molecular switch. Proceedings of the National Academy of Sciences USA.
   • (2004) An EF-hand in the sodium channel couples intracellular calcium to cardiac excitability. Nature Structural and Molecular Biology.

6. What are the molecular mechanisms that drive ubiquitin signaling?
   • (2013) Activation of UbcH5c~Ub is the result of a shift in interdomain motions of the conjugate bound to U-box E3 ligase E4B. Biochemistry
   • (2012) Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Molecular Cell.
   • (2003) Structural insights into the U-box, a domain associated with multi-ubiquitination. Nature Structural and Molecular Biology.