Diversity within the adenovirus fiber knob hypervariable loops influences primary receptor interactions

Nat Commun. 2019 Feb 14;10(1):741. doi: 10.1038/s41467-019-08599-y.


Adenovirus based vectors are of increasing importance for wide ranging therapeutic applications. As vaccines, vectors derived from human adenovirus species D serotypes 26 and 48 (HAdV-D26/48) are demonstrating promising efficacy as protective platforms against infectious diseases. Significant clinical progress has been made, yet definitive studies underpinning mechanisms of entry, infection, and receptor usage are currently lacking. Here, we perform structural and biological analysis of the receptor binding fiber-knob protein of HAdV-D26/48, reporting crystal structures, and modelling putative interactions with two previously suggested attachment receptors, CD46 and Coxsackie and Adenovirus Receptor (CAR). We provide evidence of a low affinity interaction with CAR, with modelling suggesting affinity is attenuated through extended, semi-flexible loop structures, providing steric hindrance. Conversely, in silico and in vitro experiments are unable to provide evidence of interaction between HAdV-D26/48 fiber-knob with CD46, or with Desmoglein 2. Our findings provide insight into the cell-virus interactions of HAdV-D26/48, with important implications for the design and engineering of optimised Ad-based therapeutics.

Publication types

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

MeSH terms

  • Adenoviridae Infections / metabolism*
  • Adenoviridae Infections / virology
  • Adenoviruses, Human / genetics
  • Adenoviruses, Human / metabolism*
  • Adenoviruses, Human / physiology
  • Amino Acid Sequence
  • Capsid Proteins / chemistry
  • Capsid Proteins / classification
  • Capsid Proteins / metabolism*
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein / chemistry
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein / metabolism
  • Crystallography, X-Ray
  • Genetic Variation
  • Humans
  • Membrane Cofactor Protein / chemistry
  • Membrane Cofactor Protein / metabolism
  • Models, Molecular
  • Phylogeny
  • Protein Binding
  • Protein Conformation
  • Receptors, Virus / chemistry
  • Receptors, Virus / metabolism*
  • Sequence Homology, Amino Acid


  • CD46 protein, human
  • Capsid Proteins
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Membrane Cofactor Protein
  • Receptors, Virus
  • hexon capsid protein, Adenovirus