The 2.8 Å Electron Microscopy Structure of Adeno-Associated Virus-DJ Bound by a Heparinoid Pentasaccharide

Qing Xie, John M. Spear, Alex J. Noble, Duncan R. Sousa, Nancy L. Meyer, Omar Davulcu, Fuming Zhang, Robert J. Linhardt, Scott M. Stagg, Michael Chapman

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Atomic structures of adeno-associated virus (AAV)-DJ, alone and in complex with fondaparinux, have been determined by cryoelectron microscopy at 3 Å resolution. The gene therapy vector, AAV-DJ, is a hybrid of natural serotypes that was previously derived by directed evolution, selecting for hepatocyte entry and resistance to neutralization by human serum. The structure of AAV-DJ differs from that of parental serotypes in two regions where neutralizing antibodies bind, so immune escape appears to have been the primary driver of AAV-DJ's directed evolution. Fondaparinux is an analog of cell surface heparan sulfate to which several AAVs bind during entry. Fondaparinux interacts with viral arginines at a known heparin binding site, without the large conformational changes whose presence was controversial in low-resolution imaging of AAV2-heparin complexes. The glycan density suggests multi-modal binding that could accommodate sequence variation and multivalent binding along a glycan polymer, consistent with a role in attachment, prior to more specific interactions with a receptor protein mediating entry.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalMolecular Therapy - Methods and Clinical Development
Volume5
DOIs
StatePublished - Jun 16 2017

Keywords

  • AAV
  • adeno-associated virus
  • attachment
  • electron microscopy
  • gene therapy
  • glycan
  • heparan sulfate
  • receptor
  • structure
  • vector

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine

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