The large repertoire of virulence factors from pathogens such as Yersinia spp. (plague), Shigella spp. (bacterial dysentery), Escherichia coli (enterohaemorrhagic diarrhea), Pseudomonas aeruginosa (opportunistic pneumonia) and Salmonella enterica (gastroenteritis and typhoid fever) include 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’ laboratory is using Salmonella as a model system, 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 “bottomto- top” mechanistic understanding of the pathogen’s host-cell invasion process. Since the process is a central event in several pathogenic organisms and an example of 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. Type III secretion systems translocate bacterial proteins directly into the host-cell cytosol, are composed of more than 20 proteins 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 structure is thought to serve as a conduit or channel for the passage of the 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’ lab is interested in using information gleaned from their experiments to design a novel class of antimicrobial agents that specifically target bacterial virulence mechanisms. By using computation and chemical screening, they are identifying compounds that could potentially be used to inhibit key virulence factors in pathogens that pose significant health concerns, such as infectious agents in developing nations or agents of biowarfare.

Dr. Stebbins has solved the structures of more than 15 proteins, including the cancerrelated VHL 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 (CDT, 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). His laboratory also uncovered the first common binding motif linking many virulence factors of type III secretion systems to their secretion chaperones. The structures he has identified can be used to determine how the pathogenic molecules might be most vulnerable to inactivation, and therefore effective targets for drug therapy.

CAREER

Dr. Stebbins received his bachelor’s degree in physics from Oberlin College in 1992. After working for a year as a graduate fellow in the physics department at Stony Brook University, and another year as a research assistant in Seth Darst’s lab at Rockefeller, he began his graduate research. He received his Ph.D. in biochemistry and structural biology in 1999 from Cornell University’s Weill Graduate School of Medical Sciences. Dr. Stebbins did his postdoctoral work in microbial pathogenesis at the Yale University School of Medicine, then moved to Rockefeller in 2001 when he was appointed assistant professor and head of the Laboratory of Structural Microbiology. He was named associate professor in 2006.

Dr. Stebbins received the American Society of Microbiology’s ICAAC Young Investigator Award in 2004, and the Molecular Structure Corporation’s Future Investigator Award in 2000. He was awarded the Julian R. Rachele Prize from Weill Graduate School of Medical Sciences of Cornell University in 1999.