Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus

Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):E2156-65. doi: 10.1073/pnas.1501690112. Epub 2015 Mar 30.


The discovery of African henipaviruses (HNVs) related to pathogenic Hendra virus (HeV) and Nipah virus (NiV) from Southeast Asia and Australia presents an open-ended health risk. Cell receptor use by emerging African HNVs at the stage of host-cell entry is a key parameter when considering the potential for spillover and infection of human populations. The attachment glycoprotein from a Ghanaian bat isolate (GhV-G) exhibits <30% sequence identity with Asiatic NiV-G/HeV-G. Here, through functional and structural analysis of GhV-G, we show how this African HNV targets the same human cell-surface receptor (ephrinB2) as the Asiatic HNVs. We first characterized this virus-receptor interaction crystallographically. Compared with extant HNV-G-ephrinB2 structures, there was significant structural variation in the six-bladed β-propeller scaffold of the GhV-G receptor-binding domain, but not the Greek key fold of the bound ephrinB2. Analysis revealed a surprisingly conserved mode of ephrinB2 interaction that reflects an ongoing evolutionary constraint among geographically distal and phylogenetically divergent HNVs to maintain the functionality of ephrinB2 recognition during virus-host entry. Interestingly, unlike NiV-G/HeV-G, we could not detect binding of GhV-G to ephrinB3. Comparative structure-function analysis further revealed several distinguishing features of HNV-G function: a secondary ephrinB2 interaction site that contributes to more efficient ephrinB2-mediated entry in NiV-G relative to GhV-G and cognate residues at the very C terminus of GhV-G (absent in Asiatic HNV-Gs) that are vital for efficient receptor-induced fusion, but not receptor binding per se. These data provide molecular-level details for evaluating the likelihood of African HNVs to spill over into human populations.

Keywords: emerging virus; glycoprotein; henipavirus; structure; viral attachment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ephrin-B2* / chemistry
  • Ephrin-B2* / genetics
  • Ephrin-B2* / metabolism
  • Ephrin-B3 / chemistry
  • Ephrin-B3 / genetics
  • Ephrin-B3 / metabolism
  • HEK293 Cells
  • Henipavirus Infections / genetics
  • Henipavirus Infections / metabolism*
  • Henipavirus* / chemistry
  • Henipavirus* / physiology
  • Humans
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Viral Proteins* / chemistry
  • Viral Proteins* / genetics
  • Viral Proteins* / metabolism
  • Virus Internalization*


  • Ephrin-B2
  • Ephrin-B3
  • Viral Proteins

Associated data

  • PDB/4UF7