Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structural basis of receptor usage by the engineered capsid AAV-PHP.eB.
Journal, issue, pages	Mol Ther Methods Clin Dev, Vol. 26, Page 343-354, Year 2022
Publish date	Sep 8, 2022
Authors	Seongmin Jang / Hao K Shen / Xiaozhe Ding / Timothy F Miles / Viviana Gradinaru /
PubMed Abstract	Adeno-associated virus serotype 9 (AAV9) is a promising gene therapy vector for treating neurodegenerative diseases due to its ability to penetrate the blood-brain barrier. PHP.eB was engineered ...Adeno-associated virus serotype 9 (AAV9) is a promising gene therapy vector for treating neurodegenerative diseases due to its ability to penetrate the blood-brain barrier. PHP.eB was engineered from AAV9 by insertion of a 7-amino acid peptide and point mutation of neighboring residues, thereby enhancing potency in the central nervous system. Here, we report a 2.24-Å resolution cryo-electron microscopy structure of PHP.eB, revealing conformational differences from other 7-mer insertion capsid variants. In PHP.eB, the 7-mer loop adopts a bent conformation, mediated by an interaction between engineered lysine and aspartate residues. Further, we identify PKD2 as the main AAV receptor (AAVR) domain recognizing both AAV9 and PHP.eB and find that the PHP.eB 7-mer partially destabilizes this interaction. Analysis of previously reported AAV structures together with our pull-down data demonstrate that the 7-mer topology determined by the lysine-aspartate interaction dictates AAVR binding strength. Our results suggest that PHP.eB's altered tropism may arise from both an additional interaction with LY6A and weakening of its AAVR interaction. Changing the insertion length, but not sequence, modifies PKD2 binding affinity, suggesting that a steric clash impedes AAVR binding. This research suggests improved library designs for future AAV selections to identify non-LY6A-dependent vectors and modulate AAVR interaction strength.
External links	Mol Ther Methods Clin Dev / PubMed:36034770 / PubMed Central
Methods	EM (single particle)
Resolution	2.24 - 2.9 Å
Structure data	EMDB-26417: Cryo-EM structure of AAV-PHP.eB, C1 Symmetry Method: EM (single particle) / Resolution: 2.9 Å 26453 7ud4 EMDB-26453: Cryo-EM structure of AAV-PHP.eB, I1 symmetry applied PDB-7ud4: Cryo-EM structure of AAV-PHP.eB Method: EM (single particle) / Resolution: 2.24 Å
Source	adeno-associated virus
Keywords	VIRUS / Gene therapy / AAV / capsid / blood-brain barrier / directed evolution