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 Study of Aavrh.10 Receptor and Antibody Interactions.
Journal, issue, pages	J Virol, Vol. 95, Issue 23, Page e0124921, Year 2021
Publish date	Nov 9, 2021
Authors	Mario Mietzsch / Jennifer C Yu / Jane Hsi / Paul Chipman / Felix Broecker / Zhang Fuming / Robert J Linhardt / Peter H Seeberger / Regine Heilbronn / Robert McKenna / Mavis Agbandje-McKenna /
PubMed Abstract	Recombinant adeno-associated virus (rAAV) vectors are one of the leading tools for the delivery of therapeutic genes in human gene therapy applications. For a successful transfer of their payload, ...Recombinant adeno-associated virus (rAAV) vectors are one of the leading tools for the delivery of therapeutic genes in human gene therapy applications. For a successful transfer of their payload, the AAV vectors have to circumvent potential preexisting neutralizing host antibodies and bind to the receptors of the target cells. Both of these aspects have not been structurally analyzed for AAVrh.10. Here, cryo-electron microscopy and three-dimensional image reconstruction were used to map the binding site of sulfated -acetyllactosamine (LacNAc; previously shown to bind AAVrh.10) and a series of four monoclonal antibodies (MAbs). LacNAc was found to bind to a pocket located on the side of the 3-fold capsid protrusion that is mostly conserved to AAV9 and equivalent to its galactose-binding site. As a result, AAVrh.10 was also shown to be able to bind to cell surface glycans with terminal galactose. For the antigenic characterization, it was observed that several anti-AAV8 MAbs cross-react with AAVrh.10. The binding sites of these antibodies were mapped to the 3-fold capsid protrusions. Based on these observations, the AAVrh.10 capsid surface was engineered to create variant capsids that escape these antibodies while maintaining infectivity. Gene therapy vectors based on adeno-associated virus rhesus isolate 10 (AAVrh.10) have been used in several clinical trials to treat monogenetic diseases. However, compared to other AAV serotypes little is known about receptor binding and antigenicity of the AAVrh.10 capsid. Particularly, preexisting neutralizing antibodies against capsids are an important challenge that can hamper treatment efficiency. This study addresses both topics and identifies critical regions of the AAVrh.10 capsid for receptor and antibody binding. The insights gained were utilized to generate AAVrh.10 variants capable of evading known neutralizing antibodies. The findings of this study could further aid the utilization of AAVrh.10 vectors in clinical trials and help the approval of the subsequent biologics.
External links	J Virol / PubMed:34549984 / PubMed Central
Methods	EM (single particle)
Resolution	2.71 - 7.1 Å
Structure data	24513 7rl1 EMDB-24513, PDB-7rl1: AAVrh.10-7x capsid Method: EM (single particle) / Resolution: 2.71 Å 24806 7s1w EMDB-24806, PDB-7s1w: The AAVrh.10-glycan complex Method: EM (single particle) / Resolution: 3.09 Å EMDB-24808: AAVrh.10:ADK8 Method: EM (single particle) / Resolution: 6.6 Å EMDB-24809: AAVrh.10:ADK8/9 Method: EM (single particle) / Resolution: 6.45 Å EMDB-24810: AAVrh.10:HL2381 Method: EM (single particle) / Resolution: 6.2 Å EMDB-24811: AAVrh.10:HL2383 Method: EM (single particle) / Resolution: 7.1 Å
Chemicals	ChemComp-DC: 2'-DEOXYCYTIDINE-5'-MONOPHOSPHATE / dCMPYM / Deoxycytidine monophosphate ChemComp-DA: 2'-DEOXYADENOSINE-5'-MONOPHOSPHATE / dAMPYM / Deoxyadenosine monophosphate ChemComp-GAL: beta-D-galactopyranose / Galactose
Source	adeno-associated virus
Keywords	VIRUS / Icosahedral Capsid / AAVrh.10 / capsid engineering / Adeno-associated virus / Parvovirus / Gene Therapy / capsid / glycan complex / galactose / LacNAc