|Entry||Database: EMDB / ID: 0535|
|Title||Cryo-EM Reconstruction of Protease-Activateable Adeno-Associated Virus 9 (AAV9-L001)|
|Map data||Protease-Activateable Adeno-associated Virus 9 (AAV9-L001)|
virus / Capsid protein VP1
|Function / homology||Parvovirus coat protein VP2 / Parvovirus coat protein VP1, N-terminal / Capsid/spike protein, ssDNA virus / Parvovirus coat protein VP1/VP2 / Parvovirus coat protein VP2 / Parvovirus coat protein VP1 / viral capsid / structural molecule activity / Capsid protein VP1|
Function and homology information
|Method||single particle reconstruction / cryo EM / 3.16 Å resolution|
|Authors||Bennett AB / Agbandje-Mckenna M|
|Citation||Journal: Mol. Ther. / Year: 2019|
Title: Protease-Activatable Adeno-Associated Virus Vector for Gene Delivery to Damaged Heart Tissue.
Authors: Caitlin M Guenther / Mitchell J Brun / Antonette D Bennett / Michelle L Ho / Weitong Chen / Banghe Zhu / Michael Lam / Momona Yamagami / Sunkuk Kwon / Nilakshee Bhattacharya / Duncan Sousa / Annicka C Evans / Julie Voss / Eva M Sevick-Muraca / Mavis Agbandje-McKenna / Junghae Suh
Abstract: Adeno-associated virus (AAV) has emerged as a promising gene delivery vector because of its non-pathogenicity, simple structure and genome, and low immunogenicity compared to other viruses. However, ...Adeno-associated virus (AAV) has emerged as a promising gene delivery vector because of its non-pathogenicity, simple structure and genome, and low immunogenicity compared to other viruses. However, its adoption as a safe and effective delivery vector for certain diseases relies on altering its tropism to deliver transgenes to desired cell populations. To this end, we have developed a protease-activatable AAV vector, named provector, that responds to elevated extracellular protease activity commonly found in diseased tissue microenvironments. The AAV9-based provector is initially inactive, but then it can be switched on by matrix metalloproteinases (MMP)-2 and -9. Cryo-electron microscopy and image reconstruction reveal that the provector capsid is structurally similar to that of AAV9, with a flexible peptide insertion at the top of the 3-fold protrusions. In an in vivo model of myocardial infarction (MI), the provector is able to deliver transgenes site specifically to high-MMP-activity regions of the damaged heart, with concomitant decreased delivery to many off-target organs, including the liver. The AAV provector may be useful in the future for enhanced delivery of transgenes to sites of cardiac damage.
|Validation Report||PDB-ID: 6nxe|
SummaryFull reportAbout validation report
|Date||Deposition: Feb 8, 2019 / Header (metadata) release: Mar 6, 2019 / Map release: Mar 13, 2019 / Last update: Mar 20, 2019|
|Structure viewer||EM map: |
Downloads & links
|File||emd_0535.map.gz (map file in CCP4 format, 277707 KB)|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 0.974 Å|
CCP4 map header:
-Entire Adeno-associated virus
|Entire||Name: Adeno-associated virus / Number of components: 2|
-Component #1: virus, Adeno-associated virus
|Virus||Name: Adeno-associated virus / Class: VIRION / Empty: No / Enveloped: No / Isolate: SEROTYPE|
|Species||Species: Adeno-associated virus / Strain: 9-L001|
|Source (engineered)||Expression System: Homo sapiens (human)|
-Component #2: protein, Capsid protein VP1
|Protein||Name: Capsid protein VP1 / Number of Copies: 60 / Recombinant expression: No|
|Mass||Theoretical: 60.939168 kDa|
|Source||Species: Adeno-associated virus|
|Source (engineered)||Expression System: Homo sapiens (human)|
|Specimen||Specimen state: particle / Method: cryo EM|
|Sample solution||Specimen conc.: 0.5 mg/ml / pH: 7.4|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Imaging||Microscope: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 2 e/Å2 / Illumination mode: FLOOD BEAM|
|Lens||Imaging mode: BRIGHT FIELD|
|Specimen Holder||Model: OTHER|
|Camera||Detector: DIRECT ELECTRON DE-20 (5k x 3k)|
|Processing||Method: single particle reconstruction / Number of projections: 114044|
|3D reconstruction||Resolution: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF|
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