Understanding the rhabdovirus fusion machinery Perspectives opened by dynamic structural virology Molecular and Structural...
Rhabdovirus  entry into the host cell Prototypes : rabies virus and VSV Enveloped viruses with a typical bullet shape  Gly...
The membrane fusion pathway Complete fusion Stalk Hemifusion Fusion Pore Class I Paramyxovirus F Influenza HA HIV gp160 Cl...
Rhabdovirus glycoprotein G:  The prototype of the third class  How does it work ? Internal fusion  loops Transmembrane  do...
Visualization of individual fusion events pH 7.5 <ul><li>Identification of two distinct steps  </li></ul><ul><li>during me...
Crystalline structures of VSV G TM Trimers Prefusion Postfusion Roche et al.  Science  2006 ;  Science  2007 Membrane Form...
Target membrane Viral membrane
The conformational change pathway Trimeric  prefusion  state (high pH) Trimeric postfusion state (low pH) Fusion loops Tra...
First structure of intermediates <ul><li>Chandipura virus (outbreaks of deadly encephalitis in India) </li></ul><ul><li>Tw...
Structural virology:  a french « savoir faire » <ul><ul><li>Class II fusion proteins of Chikungunya virus ( Felix Rey , In...
Perspectives <ul><li>Powerful hybrid approaches  (Cristallography, EM, SAXS, NMR…) in structural virology allow: </li></ul...
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1.4 yves gaudin

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1.4 yves gaudin

  1. 1. Understanding the rhabdovirus fusion machinery Perspectives opened by dynamic structural virology Molecular and Structural Virology Laboratory CNRS – Gif sur Yvette Yves Gaudin CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
  2. 2. Rhabdovirus entry into the host cell Prototypes : rabies virus and VSV Enveloped viruses with a typical bullet shape Glycoprotein G mediates viral entry Endosome acidification Membrane fusion Virion endocytosis Receptor recognition
  3. 3. The membrane fusion pathway Complete fusion Stalk Hemifusion Fusion Pore Class I Paramyxovirus F Influenza HA HIV gp160 Class II Alphavirus E1 Flavivirus E Native or prefusion conformation Energy Final or postfusion conformation Fusion machineries
  4. 4. Rhabdovirus glycoprotein G: The prototype of the third class How does it work ? Internal fusion loops Transmembrane domain 446 466 495 CHO CHO pH-dependent equilibrium between these different states Prefusion state Activated state Postfusion state Receptor recognition Membrane interaction pH >7 pH < 6.5 pH 7.5 pH 5.5 One glycoprotein Several conformations
  5. 5. Visualization of individual fusion events pH 7.5 <ul><li>Identification of two distinct steps </li></ul><ul><li>during membrane fusion </li></ul><ul><li>Libersou et al. J. Cell Biol. 2010 </li></ul>LIPO LIPO pH 5.5
  6. 6. Crystalline structures of VSV G TM Trimers Prefusion Postfusion Roche et al. Science 2006 ; Science 2007 Membrane Forme préfusion Protomers Prefusion Postfusion
  7. 7. Target membrane Viral membrane
  8. 8. The conformational change pathway Trimeric prefusion state (high pH) Trimeric postfusion state (low pH) Fusion loops Transmembrane domains * * Tomography Cristallography Tomography Cristallography EM SAXS Decreasing pH
  9. 9. First structure of intermediates <ul><li>Chandipura virus (outbreaks of deadly encephalitis in India) </li></ul><ul><li>Two different monomers in the asymetric unit ! </li></ul>1 1 2 2 VSV G postfusion Late intermediate VSV G prefusion Fusion loops. TM domains. Early intermediate
  10. 10. Structural virology: a french « savoir faire » <ul><ul><li>Class II fusion proteins of Chikungunya virus ( Felix Rey , Institut Pasteur) </li></ul></ul><ul><ul><li>Replication complex of influenza and Mononegavirales , HIV structural biology ( Rob Ruigrok , Winfried Weissenhorn , UVHCI, Grenoble) </li></ul></ul><ul><ul><li>Replication complex of positive strand RNA viruses such as Dengue virus, West Nile virus, SARS coronavirus ( Bruno Canard , AFMB, Marseille) </li></ul></ul>
  11. 11. Perspectives <ul><li>Powerful hybrid approaches (Cristallography, EM, SAXS, NMR…) in structural virology allow: </li></ul><ul><li>Access to the dynamics of complex viral machineries </li></ul><ul><li>Determination of the structure of intermediates that can constitute new targets for antiviral strategies </li></ul><ul><li> </li></ul>

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