Yorgo Eugene Modis PhD

Research Scientist in Molecular Biophysics and Biochemistry

Research Interests

Bacterial Infections; Biochemistry; Biophysics; Disease Resistance; Immune System; Immune System Disorders; Immunology; Infectious Diseases or Agents; Inflammatory Bowel Disease; Natural Processes Health Safety Medical; Pathogenesis; Receptors; Structural Biology; Structure or Function (Health or Safety or Medical); Vaccine

Research Summary

We study the molecular mechanisms of host-pathogen interactions using X-ray crystallography, microscopy, and other biophysical and biochemical approaches. We place a special emphasis (1) on understanding how flaviviruses such as dengue virus enter host cells, and (2) on studying the molecular basis of recognition of flaviviruses and other microbes by receptors of the innate immune system. We have gained valuable insights on the mechanism of virus entry in the host cell by determining the crystal structure of the envelope protein of dengue virus in two different conformations: before and after fusion of the viral and host-cell membranes. The structures reveal the molecular basis for fusion of the viral and host cell membrane in a class of viral fusion proteins that includes many other important human pathogens, such as yellow fever, hepatitis C and West Nile viruses. Current work in the laboratory focuses on completing our picture of membrane fusion in flaviviruses and in related enveloped viruses, and on understanding the molecular mechanisms of antibody neutralization of these viruses, using single-molecule approaches. Also, in a new set of projects, we aim to understand at the molecular level how innate immune receptors such as the Toll-like receptors and the Rig-I-like receptors recognize flaviviruses (and other microbes), and how this recognition is translated into an immune response.

Extensive Research Description

We use structural methods to study how pathogens enter cells and how they are recognized by the innate immune system. The Toll-like receptors have the remarkable ability to recognize a wide variety of pathogen-derived structural motifs using the same extracellular leucine-rich repeat architecture. We seek to understand how this fold is able to recognize such a large variety of ligands and translate this recognition event into an inflammatory signal. We also study how flaviviruses enter cells. Flaviviruses use their envelope protein, E, to bind a cellular receptor and enter an endosome. The reduced pH of the endosome triggers a conformational rearrangement in E, inducing the viral and host-cell membranes to fuse. Our structures of E in the pre- and postfusion states suggest a mechanism for membrane fusion, but some aspects of this key fusion remain unclear. Completing our picture of the fusion process will help us design new antiviral therapeutics.

Selected Publications

  • Berke IC, Modis Y (2012) MDA5 cooperatively forms dimers and ATP-sensitive filaments upon binding double-stranded RNA. EMBO J 31:1714-26.
  • Li Y, Berke IC, Modis Y (2012) DNA binding to proteolytically activated TLR9 is sequence-independent and enhanced by DNA curvature. EMBO J 31:919-31
  • Zhou k, Kanai R, Lee P, Wang HW, Modis Y (2012) Toll-like receptor 5 forms asymmetric dimers in the absence of flagellin. J Struct Biol 77:402-9.
  • Kucera K, Harrison LM, Cappello M, Modis Y (2011). Ancylostoma ceylanicum Excretory-Secretory Protein 2 Adopts a Netrin-Like Fold and Defines a Novel Family of Nematode Proteins. J Mol Biol 408:9-17
  • Kucera K, Koblansky AA, Saunders L, Frederick K, De La Cruz E, Ghosh S, Modis Y (2010). Structure-based analysis of Toxoplasma gondii profilin: a parasite-specific motif is required for recognition by Toll-like receptor 11. J Mol Biol 403:616-29.
  • Nayak V, Dessau M, Kucera K, Anthony K, Ledizet M, Modis Y (2009) Crystal structure of dengue type 1 envelope protein in the postfusion conformation and its implication for receptor binding, membrane fusion and antibody recognition. J Virol 83:4438-44
  • Kanai R, Kar K, Anthony K, Gould LH, Ledizet M, Fikrig E, Marasco WA, Koski RA, Modis Y (Nov 2006) Crystal structure of west nile virus envelope glycoprotein reveals viral surface epitopes., Journal of virology, 80(22)11000-8
  • Modis, Y., Ogata, S., Clements, D., and Harrison, S.C. (2004). Structure of the dengue virus envelope protein after membrane fusion. Nature 427:313-319.

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