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YORGO MODIS
The underlying objective in this laboratory is to understand fundamental biological processes by obtaining structural information on the molecules that effect them. We focus on the molecular mechanisms of viral and bacterial pathogenesis, with a particular emphasis on host-pathogen recognition.
1. Mechanisms of flaviviral entry into cells
Flaviviruses use their envelope protein, E, to bind a receptor and enter cells. Viral entry occurs when the reduced pH of an endosome triggers a conformational rearrangement in E, which induces fusion of the viral and host-cell membranes. Building on our structural studies of E from dengue and West Nile viruses in the pre- and postfusion states, we aim to complete our picture of flaviviral membrane fusion by determining the structures of the full-length E ectodomain. We also aim to determine the structure of E in complex with various peptides with therapeutic antiviral properties. Our work will provide a framework for the rational design and screening of drugs that inhibit viral entry.
There are currently no treatments or vaccines available for flaviviruses such as West Nile or dengue virus, which are both emerging global health threats. Vaccine design has been hampered by the high variability of most neutralizing epitopes and by antibody-dependent enhancement of infection due to the cross-reactivity between serotypes of antibodies at sub-neutralizing concentrations, which is thought to be one of the major causes of mortality due to dengue fever. In an effort to guide vaccine design, we will study the structural basis for neutralization by antibodies that bind conserved epitopes in flaviviral envelope proteins.
Our work on flaviviruses is part of an ongoing collaboration with Prof. Erol Fikrig (Yale School of Medicine) and L2 Diagnostics, Inc.
2. Structural basis of pathogen recognition by the innate immune system
Most organisms rely on an innate immune system as their first line of defense against infection. Within the innate immune system, the Toll-like receptors (TLRs), a family of evolutionarily ancient receptors found on the surface of many cell types, are critical for pathogen recognition outside the cell. About 12 TLRs recognize structures specific to pathogens, such as bacterial cell wall components, bacterial filament proteins, or certain types of nucleic acid. This recognition event initiates a signal inside the cell, which induces the rapid secretion of antimicrobial and inflammatory proteins. Inside the cell, the NOD proteins and RNA helicases such as MDA5 recognize similar pathogen-associated structures to those recognized by TLRs. Remarkably, given the structural diversity of the structures that they recognize, all TLRs and NODs rely on a "leucine-rich repeat" (LRR) domain to recognize pathogen-associated structures.
The overall goal of our research program on innate immune sensors is to understand how they recognize conserved molecular patterns in pathogens, and how this recognition is translated into an innate immune response. Our structural approach will provide unique insights into these important processes. First, we aim to determine the structure of one or more TLR-ligand complexes, by X-ray crystallography. Alternative crystallization targets are NOD-ligand or helicase-RNA complexes. We propose to use novel protein expression techniques to maximize protein yields. Our structures will likely define novel principles of molecular recognition. By revealing the conformational changes associated with ligand binding, the structures will provide insight on how pathogen recognition is translated into a signal in the cell that elicits an immune response. Our work will also guide efforts to design synthetic agonists or antagonists with immunomodulatory properties. Such compounds would have a wide range of medical applications, particularly as vaccine adjuvants or anti-inflammatory therapeutics.
This work will benefit from collaborations with Prof. Ruslan Medzhitov and Prof. Sankar Ghosh (Yale School of Medicine).
Selected Publications
Modis, Y., Ogata, S., Clements, D. and Harrison, S.C. A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc. Natl. Acad. Sci. U.S.A. 100, 6986-6991 (2003)
Modis, Y., Ogata, S., Clements, D. and Harrison, S.C. Structure of the dengue virus envelope protein after membrane fusion. Nature 427, 313-319 (2004)
Modis, Y., Ogata, S., Clements, D. and Harrison, S.C. Variable surface epitopes in the crystal structure of dengue virus type 3 envelope glycoprotein. J. Virol. 79, 1223-1231 (2005)
Choe, J., Kelker, M.S. and Wilson, I.A. Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309, 581-585 (2005)
Kanai, R., Kar, K., Anthony, K., Gould, L.H., Ledizet, M., Fikrig, E., Koski, R.A. and Modis, Y. Crystal structure of West Nile virus envelope glycoprotein reveals viral surface epitopes. J. Virol. 80, 11000-11008 (2006)
Last Updated 12-18-06
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