3J1Q

Structure of AAV-DJ, a Retargeted Gene Therapy Vector: Cryo-Electron Microscopy at 4.5A resolution

Summary for 3J1Q

• Entry DOI: 10.2210/pdb3j1q/pdb
• EMDB information: 5415
• Descriptor: Adeno-associated virus DJ (1 entity in total)
• Functional Keywords: gene therapy, virus
• Biological source: Adeno-associated virus
• Total number of polymer chains: 1
• Total formula weight: 82008.41

Authors

Lerch, T.F.,O'Donnell, J.K.,Meyer, N.L.,Xie, Q.,Taylor, K.A.,Stagg, S.M.,Chapman, M.S. (deposition date: 2012-04-30, release date: 2012-08-22, Last modification date: 2024-02-21)

Primary citation

Lerch, T.F.,O'Donnell, J.K.,Meyer, N.L.,Xie, Q.,Taylor, K.A.,Stagg, S.M.,Chapman, M.S.
Structure of AAV-DJ, a retargeted gene therapy vector: cryo-electron microscopy at 4.5 A resolution.
Structure, 20:1310-1320, 2012

PubMed Abstract: AAV-DJ, a leading candidate vector for liver gene therapy, was created through random homologous recombination followed by directed evolution, selecting for in vivo liver tropism and resistance to in vitro immune neutralization. Here, the 4.5 Å resolution cryo-EM structure is determined for the engineered AAV vector, revealing structural features that illuminate its phenotype. The heparan sulfate receptor-binding site is little changed from AAV-2, and heparin-binding affinity is similar. A loop that is antigenic in other serotypes has a unique conformation in AAV-DJ that would conflict with the binding of an AAV-2 neutralizing monoclonal antibody. This is consistent with increased resistance to neutralization by human polyclonal sera, raising the possibility that changed tropism may be a secondary effect of altered immune interactions. The reconstruction exemplifies analysis of fine structural changes and the potential of cryo-EM, in favorable cases, to characterize mutant or ligand-bound complexes.

PubMed: 22727812
DOI: 10.1016/j.str.2012.05.004

Experimental method

ELECTRON MICROSCOPY (4.5 Å)