The Modis Lab Research
Our underlying objective is to understand fundamental biological processes by obtaining structural information on the molecules that effect them. We focus on viral and bacterial pathogenesis, with a particular emphasis on the entry of enveloped viruses and other pathogens into host cells and the recognition of pathogen-associated structures by the innate immune system.
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. 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 is in collaborations with Prof. Sankar Ghosh (Columbia University).
3. Technical Approach
We use a variety of structural, biophysical and biochemical techniques to characterize the molecules we are interested in. Our primary tool for determining atomic details is X-ray crystallography. We express our proteins in insect, mammalian or bacterial cultures, purify them to homogeneity and high concentrations, and grow crystals. When crystals are irradiated with X-rays, they produce diffraction patterns that can be used to determine the three-dimensional structure of the crystallized molecule at atomic resolution. Recent work on proteins that fail to crystallize employs Small Angle X-ray Scattering (SAXS) or electron microscopy to determine low resolution shape information that helps guide further experiments or provides context for high resolution structures of smaller fragments.
The lab is also utilizing single-molecule fluorescence microscopy, analytical ultracentrifugation (AUC), isothermal calorimetry (ITC), molecular modeling and various spectroscopic techniques to understand the mechanisms of the proteins being studied.
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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)
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)
Nayak, V., Dessau, M., Kucera, K., Anthony, K., Ledizet, M. and Modis, Y. Crystal structure of dengue virus type 1 envelope protein in the postfusion conformation and its implications for membrane fusion. J. Virol. 83, 4338-4344 (2009)
Fogel, A.I., Li, Y., Giza, J., Wang, Q., Lam, T.T., Modis, Y. and Biederer, T. N-glycosylation at the SynCAM (synaptic cell adhesion molecule) immunoglobulin interface modulates synaptic adhesion. J. Biol. Chem. 285, 34864-34874 (2010)
Kucera, K., Koblansky, A.A., Saunders, L.P., Frederick, K.B., De La Cruz, E.M., Ghosh, S. and Modis Y. J. Mol. Biol. 403, 616-629 (2010)
A complete list of publications can be found HERE.