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 S. Chapman

Research output: Contribution to journalArticlepeer-review

14 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

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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