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Structural basis of Nipah and Hendra virus attachment to their cell-surface receptor ephrin-B2

Nature Structural & Molecular Biology volume 15, pages 567–572 (2008)Cite this article

Abstract

Nipah and Hendra viruses are emergent paramyxoviruses, causing disease characterized by rapid onset and high mortality rates, resulting in their classification as Biosafety Level 4 pathogens. Their attachment glycoproteins are essential for the recognition of the cell-surface receptors ephrin-B2 (EFNB2) and ephrin-B3 (EFNB3). Here we report crystal structures of both Nipah and Hendra attachment glycoproteins in complex with human EFNB2. In contrast to previously solved paramyxovirus attachment complexes, which are mediated by sialic acid interactions, the Nipah and Hendra complexes are maintained by an extensive protein-protein interface, including a crucial phenylalanine side chain on EFNB2 that fits snugly into a hydrophobic pocket on the viral protein. By analogy with the development of antivirals against sialic acid binding viruses, these results provide a structural template to target antiviral inhibition of protein-protein interactions.

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Figure 1: NiV-G−EFNB2 and HeV-G−EFNB2 complex structures.
Figure 2: Comparison of protein-protein and protein-sugar interactions required for paramyxovirus attachment and fusion.
Figure 3: Conformational changes that occur to the EFNB2 G-H loop upon receptor binding.
Figure 4: Points of molecular specificity in the HNV-G−EFNB2 interaction.

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Acknowledgements

We are grateful for the help of W. Lu in tissue culture, K. Harlos for data collection, C. O'Callaghan for discussions and the staff of beamlines ID14.2 and ID23.1 at the European Synchotron Radiation Facility for assistance. This work was funded by the Wellcome Trust, Medical Research Council, Royal Society, Cancer Research UK and Spine2 Complexes (FP6-RTD-031220).

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Authors and Affiliations

  1. Division of Structural Biology, University of Oxford, Henry Wellcome Building of Genomic Medicine, Roosevelt Drive, Oxford, OX3 7BN, UK

    Thomas A Bowden, A Radu Aricescu, Robert J C Gilbert, Jonathan M Grimes, E Yvonne Jones & David I Stuart

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Contributions

T.A.B., A.R.A., J.M.G., E.Y.J. and D.I.S. contributed to the design of the project and preparation of the manuscript; T.A.B. was responsible for Kd determination. T.A.B. and A.R.A. were responsible for cloning and construct design; T.A.B. expressed, purified and crystallized the HNV-G complexes; T.A.B., J.M.G. and D.I.S. contributed to X-ray data collection and solving the structure of NiV-G−EFNB2 and HeV-G−EFNB2; T.A.B. and R.J.C.G. performed AUC analysis of NiV-G.

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Correspondence to David I Stuart.

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Bowden, T., Aricescu, A., Gilbert, R. et al. Structural basis of Nipah and Hendra virus attachment to their cell-surface receptor ephrin-B2. Nat Struct Mol Biol 15, 567–572 (2008). https://doi.org/10.1038/nsmb.1435

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