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Publication Abstract from PubMed

Atomic structures of adeno-associated virus (AAV)-DJ, alone and in complex with fondaparinux, have been determined by cryoelectron microscopy at 3 A 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.

The 2.8 A Electron Microscopy Structure of Adeno-Associated Virus-DJ Bound by a Heparinoid Pentasaccharide.,Xie Q, Spear JM, Noble AJ, Sousa DR, Meyer NL, Davulcu O, Zhang F, Linhardt RJ, Stagg SM, Chapman MS Mol Ther Methods Clin Dev. 2017 Mar 8;5:1-12. doi: 10.1016/j.omtm.2017.02.004., eCollection 2017 Jun 16. PMID:28480299^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.