Giuseppe
Emeritus
Host cell recognition by the henipaviruses: Crystal structures of the Nipah G attachment glycoprotein and its complex with ephrin-B3
Kai Xu*, Kanagalaghatta R. Rajashankar?, Yee-Peng Chan?, Juha P. Himanen*, Christopher C. Broder?, and Dimitar B. Nikolov*,?
-Author Affiliations
*Structural Biology Program, Memorial Sloan?Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; ?Northeastern Collaborative Access Team, Advanced Photon Source, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439; and ?Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814 - Communicated by Bernard Moss, National Institutes of Health, Bethesda, MD, May 19, 2008 (received for review May 15, 2008)
Abstract
Nipah virus (NiV) and Hendra virus are the type species of the highly pathogenic paramyxovirus genus Henipavirus, which can cause severe respiratory disease and fatal encephalitis infections in humans, with case fatality rates approaching 75%.
NiV contains two envelope glycoproteins, the receptor-binding G glycoprotein (NiV-G) that facilitates attachment to host cells and the fusion (F) glycoprotein that mediates membrane merger.
The henipavirus G glycoproteins lack both hemagglutinating and neuraminidase activities and, instead, engage the highly conserved ephrin-B2 and ephrin-B3 cell surface proteins as their entry receptors.
Here, we report the crystal structures of the NiV-G both in its receptor-unbound state and in complex with ephrin-B3, providing, to our knowledge, the first view of a paramyxovirus attachment complex in which a cellular protein is used as the virus receptor.
Complex formation generates an extensive protein?protein interface around a protruding ephrin loop, which is inserted in the central cavity of the NiV-G β-propeller.
Analysis of the structural data reveals the molecular basis for the highly specific interactions of the henipavirus G glycoproteins with only two members (ephrin-B2 and ephrin-B3) of the very large ephrin family and suggests how they mediate in a unique fashion both cell attachment and the initiation of membrane fusion during the virus infection processes.
The structures further suggest that the NiV-G/ephrin interactions can be effectively targeted to disrupt viral entry and provide the foundation for structure-based antiviral drug design.
crystallography viral attachment
Footnotes
?To whom correspondence should be addressed. E-mail: nikolovd@mskcc.org
Author contributions: K.X. and D.B.N. designed research; K.X. and K.R.R. performed research; Y.-P.C., J.P.H., and C.C.B. contributed new reagents/analytic tools; K.X., K.R.R., C.C.B., and D.B.N. analyzed data; and K.X., C.C.B., and D.B.N. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3D11 for NiV-G and 3D12 for NiV-G/ephrin-B3).
This article contains supporting information online at www.pnas.org/cgi/content/full/0804797105/DCSupplemental.
Freely available online through the PNAS open access option.
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http://www.pnas.org/content/105/29/9953.short?rss=1
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Kai Xu*, Kanagalaghatta R. Rajashankar?, Yee-Peng Chan?, Juha P. Himanen*, Christopher C. Broder?, and Dimitar B. Nikolov*,?
-Author Affiliations
*Structural Biology Program, Memorial Sloan?Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; ?Northeastern Collaborative Access Team, Advanced Photon Source, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439; and ?Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814 - Communicated by Bernard Moss, National Institutes of Health, Bethesda, MD, May 19, 2008 (received for review May 15, 2008)
Abstract
Nipah virus (NiV) and Hendra virus are the type species of the highly pathogenic paramyxovirus genus Henipavirus, which can cause severe respiratory disease and fatal encephalitis infections in humans, with case fatality rates approaching 75%.
NiV contains two envelope glycoproteins, the receptor-binding G glycoprotein (NiV-G) that facilitates attachment to host cells and the fusion (F) glycoprotein that mediates membrane merger.
The henipavirus G glycoproteins lack both hemagglutinating and neuraminidase activities and, instead, engage the highly conserved ephrin-B2 and ephrin-B3 cell surface proteins as their entry receptors.
Here, we report the crystal structures of the NiV-G both in its receptor-unbound state and in complex with ephrin-B3, providing, to our knowledge, the first view of a paramyxovirus attachment complex in which a cellular protein is used as the virus receptor.
Complex formation generates an extensive protein?protein interface around a protruding ephrin loop, which is inserted in the central cavity of the NiV-G β-propeller.
Analysis of the structural data reveals the molecular basis for the highly specific interactions of the henipavirus G glycoproteins with only two members (ephrin-B2 and ephrin-B3) of the very large ephrin family and suggests how they mediate in a unique fashion both cell attachment and the initiation of membrane fusion during the virus infection processes.
The structures further suggest that the NiV-G/ephrin interactions can be effectively targeted to disrupt viral entry and provide the foundation for structure-based antiviral drug design.
crystallography viral attachment
Footnotes
?To whom correspondence should be addressed. E-mail: nikolovd@mskcc.org
Author contributions: K.X. and D.B.N. designed research; K.X. and K.R.R. performed research; Y.-P.C., J.P.H., and C.C.B. contributed new reagents/analytic tools; K.X., K.R.R., C.C.B., and D.B.N. analyzed data; and K.X., C.C.B., and D.B.N. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3D11 for NiV-G and 3D12 for NiV-G/ephrin-B3).
This article contains supporting information online at www.pnas.org/cgi/content/full/0804797105/DCSupplemental.
Freely available online through the PNAS open access option.
-
http://www.pnas.org/content/105/29/9953.short?rss=1
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