Structure of adenovirus type 21 knob in complex with CD46 reveals key differences in receptor contacts among species B adenoviruses

J Virol. 2010 Apr;84(7):3189-200. doi: 10.1128/JVI.01964-09. Epub 2010 Jan 13.

Abstract

The complement regulation protein CD46 is the primary attachment receptor for most species B adenoviruses (Ads). However, significant variability exists in sequence and structure among species B Ads in the CD46-binding regions, correlating with differences in affinity. Here, we report a structure-function analysis of the interaction of the species B Ad21 knob with the two N-terminal repeats SCR1 and SCR2 of CD46, CD46-D2. We have determined the structures of the Ad21 knob in its unliganded form as well as in complex with CD46-D2, and we compare the interactions with those observed for the Ad11 knob-CD46-D2 complex. Surface plasmon resonance measurements demonstrate that the affinity of Ad21 knobs for CD46-D2 is 22-fold lower than that of the Ad11 knob. The superposition of the Ad21 and Ad11 knob structures in complex with CD46-D2 reveals a substantially different binding mode, providing an explanation for the weaker binding affinity of the Ad21 knob for its receptor. A critical difference in both complex structures is that a key interaction point, the DG loop, protrudes more in the Ad21 knob than in the Ad11 knob. Therefore, the protruding DG loop does not allow CD46-D2 to approach the core of the Ad21 knob as closely as in the Ad11 knob-CD46-D2 complex. In addition, the engagement of CD46-D2 induces a conformational change in the DG loop in the Ad21 knob but not in the Ad11 knob. Our results contribute to a more profound understanding of the CD46-binding mechanism of species B Ads and have relevance for the design of more efficient gene delivery vectors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviruses, Human / chemistry*
  • Adenoviruses, Human / classification
  • Adenoviruses, Human / physiology
  • Amino Acid Sequence
  • Capsid Proteins / chemistry*
  • Membrane Cofactor Protein / chemistry*
  • Membrane Cofactor Protein / metabolism
  • Molecular Sequence Data
  • Protein Conformation
  • Receptors, Virus / chemistry*
  • Surface Plasmon Resonance
  • Virus Attachment*

Substances

  • Capsid Proteins
  • Membrane Cofactor Protein
  • Receptors, Virus