Host cell recognition by the henipaviruses: Crystal structures of the Nipah G attachment glycoprotein and its complex with ephrin-B3

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 proteinprotein interface around a protruding ephrin loop, which is inserted in the central cavity of the NiV-G ␤-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

Stimulation of Nipah Fusion: Small Intradomain Changes Trigger Extensive Interdomain Rearrangements

“…2) (27). In the case of the Nipah G RBD, the root mean square deviation (RMSD) between the x-ray structures of its apo and ephrin-bound states is <1 Å (25,26). A similar result also ensues from subjecting these x-ray structures to all-atom molecular dynamics (MD) simulations at physiological temperature (28,29).…”

“…Firstly, x-ray structures are available for the isolated Nipah RBD as well as its complex with ephrin (25,26). Secondly, both the ephrin-free and ephrin-bound structures of Nipah RBD have been subjected to MD at physiological temperature, and have been found to be stable (28,29).…”

“…4.5.3 (37). Temperature is maintained at 310 K using FIGURE 2 X-ray structures (25,26,58,59) of representative RBDs belonging to the three subfamilies of paramyxovirus receptor binding proteins (HN, H, and G). In each case, the x-ray structure of the receptor-free state (blue) is superimposed over the structure of the receptor-bound state (red), and the RMSDs between the backbone atoms of these structures are indicated.…”

“…The receptor binding sites are located in the C-terminal portion of the ectodomain, and are >2 nm away from the F activation site. X-ray crystallography indicates that the C-terminal portion of each of the four monomers of the tetramer fold into separate b-propeller-like structures with central cavities that serve as binding sites for ephrins (25,26). These ephrin (or receptor) binding domains (RBDs) are arranged about each other as a dimer-of-dimers, with the FAD serving as a twofold axis of symmetry (5).…”

Structural and functional characterization of neuraminidase-like molecule N10 derived from bat influenza A virus

“…A recent study revealed that bats are hosts to major viral pathogens from the Paramyxoviridae family (31); thus, we compared the influenza virus N10 with the important attachment glycoprotein (also known as the "vestigial NA") of several key paramyxoviruses. In terms of both the sequence and overall structure, N10 differs dramatically from the measles virus hemagglutinin (MV-H) (32), Nipah virus G protein (NiV-G) (33), and Hendra virus G protein (HeV-G) (34) (Table S2 and Fig. S2).…”