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

Title: The 2.8 Å Electron Microscopy Structure of Adeno-Associated Virus-DJ Bound by a Heparinoid Pentasaccharide.
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Name(s): Xie, Qing, author
Spear, John M, author
Noble, Alex J, author
Sousa, Duncan R, author
Meyer, Nancy L, author
Davulcu, Omar, author
Zhang, Fuming, author
Linhardt, Robert J, author
Stagg, Scott M, author
Chapman, Michael S, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2017-03-08
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_pmch_28480299 (IID), 10.1016/j.omtm.2017.02.004 (DOI), PMC5415311 (PMCID), 28480299 (RID), 28480299 (EID), S2329-0501(17)30044-X (PII)
Keywords: AAV, Adeno-associated virus, Attachment, Electron microscopy, Gene therapy, Glycan, Heparan sulfate, Receptor, Structure, Vector
Grant Number: R01 GM038060, R01 GM066875, R01 GM086892, S10 RR025080
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415311.
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_28480299
Host Institution: FSU
Is Part Of: Molecular therapy. Methods & clinical development.
2329-0501
Issue: vol. 5

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Xie, Q., Spear, J. M., Noble, A. J., Sousa, D. R., Meyer, N. L., Davulcu, O., … Chapman, M. S. (2017). The 2.8 Å Electron Microscopy Structure of Adeno-Associated Virus-DJ Bound by a Heparinoid Pentasaccharide. Molecular Therapy. Methods & Clinical Development. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_28480299