Structural basis for Rep-mediated adeno-associated virus packaging
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Adeno-associated viruses (AAVs) are parvoviruses utilized as gene therapy vectors. However, the AAV packaging mechanism is unresolved at the molecular level, creating a bottleneck for vector manufacturing, safety, and efficacy. Here, cryo-EM structures of the Rep helicase packaging motor in complex with the packaging marker DNA (ITR) and the Rep-AAV8 capsid complex are presented. Rep-ITR complexes reveal dynamic oligomeric states on the DNA, elucidating the strand separation mechanism coupled to its ATPase cycle. We observe Rep preferentially bound to empty capsids, with a binding interface likely conserved across the virus family. This complex also unveils a cryptic capsid ATP-binding site which, alongside Rep binding, triggers structural rearrangements priming the capsid for packaging. Collectively, these findings advance the understanding of Rep-mediated packaging, with significant implications for parvovirus virology and viral vector design.
Date Issued
2026-03-24
Date Acceptance
2026-02-04
Citation
Cell Reports, 2026, 45 (3)
ISSN
2211-1247
Publisher
Elsevier BV
Journal / Book Title
Cell Reports
Volume
45
Issue
3
Copyright Statement
© 2026 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Publication Status
Published
Article Number
117044
Date Publish Online
2026-03-05