Comparative structural, biophysical, and receptor binding study of true type and wild type AAV2

•Structurally, the VP topology and capsid morphology of AAV-TT is homologous to AAV2.•AAV-TT differs by 14 amino acids from AAV2, two of which, S585R and T588R are essential for HSPG binding.•AAV-TT is significantly more stable than AAV2 throughout the endo/lysosomal pathway and suggests a potential to withstand destabilizing conditions during infection.•Identified residues that can be engineered, they do not affect the capsid structure, but result in vectors with improved function such as escape of neutralizing antibodies.