9P4Q

Cryo-EM structure of AAV.CAP-B10 complexed to AAVR-PKD2

Summary for 9P4Q

• Entry DOI: 10.2210/pdb9p4q/pdb
• EMDB information: 71278
• Descriptor: Capsid protein VP1, Dyslexia-associated protein KIAA0319-like protein (2 entities in total)
• Functional Keywords: aav, receptor, complex, liver detarget, virus
• Biological source: Adeno-associated virus; More
• Total number of polymer chains: 2
• Total formula weight: 95749.59

Authors

Brittain, T.J.,Jang, S. (deposition date: 2025-06-17, release date: 2026-04-15, Last modification date: 2026-05-20)

Primary citation

Brittain, T.J.,Jang, S.,Coughlin, G.M.,Hoang, J.D.,Barcelona, B.H.,Giriat, I.,Ristic, F.,Appling, N.,Chossis, C.P.M.A.,Shay, T.F.,Gradinaru, V.
Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids.
Mol.Ther., 2026

PubMed Abstract: Developing effective vectors for gene therapy requires accurate on-target coverage while minimizing off-target transduction that can lead to adverse events. In mice, the engineered capsid PHP.eB shows enhanced brain transduction, while the further engineered CAP-B10 is also de-targeted from astrocytes and liver. Here, we solved cryoelectron microscopy (cryo-EM) structures of CAP-B10 and its complex with the adeno-associated virus receptor (AAVR) domain PKD2, at 2.22- and 2.20-Å resolutions, respectively. These structures reveal a motif that hinders AAVR binding, which we confirmed by measuring affinities. We showed that this motif is transferable to other capsids by solving cryo-EM structures of AAV9-X1, at 3.09 Å, and AAV9-X1.1 without and with PKD2, at 2.51 and 2.18 Å, respectively. Using this structural information, we designed and validated novel AAV variants with reduced liver and altered brain cell tropism in vivo. Overall, we provide a framework for using structural information to guide rational engineering of gene delivery vectors to achieve safe and effective delivery.

PubMed: 41906393
DOI: 10.1016/j.ymthe.2026.03.030

Experimental method

ELECTRON MICROSCOPY (2.2 Å)