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

Xie, Q.
Spear, J.
Noble, A.
Sousa, D.
Meyer, N.
Davulcu, O.
Zhang, F.
Stagg, S.
Chapman, M.
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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The 2.8 Å Electron Microscopy Structure of Adeno-Associated Virus-DJ Bound by a Heparanoid Pentasaccharide Q. Xie, J. Spear, A. Noble, D. Sousa, N. Meyer, O. Davulcu, F. Zhang, R. Linhardt, S. Stagg, M. Chapman, Molecular Therapy - Methods & Clinical Development, 5, 1-12, 2017.
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.
Molecular Therapy - Methods & Clinical Development, 5, 1-12
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The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
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Rensselaer Polytechnic Institute, Troy, NY
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