Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR
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- Nancy L Meyer
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
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- Guiqing Hu
- Institute Molecular Biophysics, Florida State University, Tallahassee, United States
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- Omar Davulcu
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
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- Qing Xie
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
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- Alex J Noble
- Institute Molecular Biophysics, Florida State University, Tallahassee, United States
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- Craig Yoshioka
- OHSU Center for Spatial Systems Biomedicine, Portland, United States
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- Drew S Gingerich
- OHSU Center for Spatial Systems Biomedicine, Portland, United States
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- Andrew Trzynka
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
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- Larry David
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
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- Scott M Stagg
- Institute Molecular Biophysics, Florida State University, Tallahassee, United States
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- Michael Stewart Chapman
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
説明
<jats:p>Adeno-associated virus (AAV) vectors are preeminent in emerging clinical gene therapies. Generalizing beyond the most tractable genetic diseases will require modulation of cell specificity and immune neutralization. Interactions of AAV with its cellular receptor, AAVR, are key to understanding cell-entry and trafficking with the rigor needed to engineer tissue-specific vectors. Cryo-electron tomography shows ordered binding of part of the flexible receptor to the viral surface, with distal domains in multiple conformations. Regions of the virus and receptor in close physical proximity can be identified by cross-linking/mass spectrometry. Cryo-electron microscopy with a two-domain receptor fragment reveals the interactions at 2.4 Å resolution. AAVR binds between AAV’s spikes on a plateau that is conserved, except in one clade whose structure is AAVR-incompatible. AAVR’s footprint overlaps the epitopes of several neutralizing antibodies, prompting a re-evaluation of neutralization mechanisms. The structure provides a roadmap for experimental probing and manipulation of viral-receptor interactions.</jats:p>
収録刊行物
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- eLife
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eLife 8 2019-05-22
eLife Sciences Publications, Ltd
