Heads of Laboratories
Laboratory of Structural Microbiology
Bacterial pathogens that have coevolved with their hosts display remarkably sophisticated adaptations, often engaging their hosts in intricate biochemical cross talk. Using techniques from biochemistry, microbial cell biology, and x-ray crystallography, Dr. Stebbins’s laboratory studies how bacterial virulence factors target hosts, and how they secrete proteins into the host cell, with the eventual goal of designing novel antibiotics.
The large repertoire of virulence factors from pathogens such as Yersinia species (plague), Shigella species (bacterial dysentery), Escherichia coli (enterohaemorrhagic diarrhea), Pseudomonas aeruginosa (opportunistic pneumonia), and Salmonella enterica (gastroenteritis and typhoid fever) includes protein tyrosine phosphatases, protein kinases, lipid phosphatases, and other effectors. Structural work with the molecules that make up these virulence factors promises to illuminate many aspects of the host-pathogen interaction and to provide new tools for understanding a variety of basic eukaryotic cellular processes.
Dr. Stebbins’s laboratory is examining effector biochemical and pathogenic activity via structural biology and structure-based mutagenesis in combination with in vitro and in vivo assays. Their ultimate goal is to synthesize a mechanistic understanding of the pathogen’s host-cell invasion process. Because of the subtle and sophisticated biochemical cross talk between host and pathogen, it represents an ideal field of study for infectious disease and structural biology.
Another effort in the lab is the structural characterization of the type III secretion apparatus used by many bacteria. Composed of more than 20 proteins, type III secretion systems translocate bacterial proteins directly into the host-cell cytosol, and are closely related to the flagellar assembly apparatus. Although the basic components of these incredibly complex systems have been identified, the actual mechanisms of protein secretion are poorly understood.
A subset of the type III secretion components forms a supramolecular structure known as the needle complex that spans the bacterial envelope. This “organic nanosyringe” is thought to serve as a conduit or channel for secreted proteins through the bacterial envelope on their route to the host-cell cytosol. Because the secretion of bacterial effectors is central to virulence in these organisms, studying their export apparatus is key to understanding type III secretion systems.
Bacteria are constantly evolving and exchanging mechanisms to resist antibiotics, so there is a great need for novel pharmacological interventions in bacterial infection. Dr. Stebbins’s lab is interested in using information gleaned from experiments to design a novel class of antimicrobial agents that specifically target bacterial virulence mechanisms.
Dr. Stebbins has solved the structures of numerous medically relevant proteins, including the cancer-related Von Hippel-Lindau tumor suppressor, the oncogenic chaperone Hsp90, and a growing number of bacterial toxins. His research led to the first structural renderings of cytolethal distending toxin (a widespread genotoxin found in a number of disease-causing bacteria), AvrPtoB (a bacterial mimic of host E3 ubiquitin ligases) and YpkA (a critical virulence factor from the plague pathogen), and the first structural information of the virulence factor CagA of Helicobacter pylori. The structures he has identified can be used to determine how the pathogenic molecules might be deactivated and are therefore effective targets for drug therapy.
B.A. in physics, 1992
Ph.D. in biochemistry and structural biology, 1999
Sanford I. Weill Graduate School of Medical Sciences of
Yale University School of Medicine, 1999–2001
Assistant Professor, 2001–2006
Associate Professor, 2006–
The Rockefeller University
ICAAC Young Investigator Award, American Society for Microbiology, 2004
National Institutes of Health EUREKA Award, 2008
Nešic D. et al. Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2. Proc. Natl. Acad. Sci. U.S.A. 111, 1562–1567 (2014).
Quezada, C.M. et al. A family of Salmonella virulence factors functions as a distinct class of autoregulated E3 ubiquitin ligases. Proc. Natl. Acad. Sci. U.S.A. 106, 4864–4869 (2009).
Prehna, G. et al. Yersinia virulence depends on mimicry of host Rho-family nucleotide dissociation inhibitors. Cell 126, 869–880 (2006).
Janjusevic, R. et al. A bacterial inhibitor of host programmed cell death defenses is an E3 ubiquitin ligase. Science 311, 222–226 (2006).
Nešic, D. et al. Assembly and function of a bacterial genotoxin. Nature 429, 429–433 (2004).
Dr. Stebbins is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Chemical Biology.