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TitleStructural basis for the neurotropic AAV9 and the engineered AAVPHP.eB recognition with cellular receptors.
Journal, issue, pagesMol Ther Methods Clin Dev, Vol. 26, Page 52-60, Year 2022
Publish dateSep 8, 2022
AuthorsGuangxue Xu / Ran Zhang / Huapeng Li / Kaixin Yin / Xinyi Ma / Zhiyong Lou /
PubMed AbstractClade F adeno-associated virus (AAV) 9 has been utilized as therapeutic gene delivery vector, and it is capable of crossing blood brain barrier (BBB). Recently, an AAV9-based engineering serotype ...Clade F adeno-associated virus (AAV) 9 has been utilized as therapeutic gene delivery vector, and it is capable of crossing blood brain barrier (BBB). Recently, an AAV9-based engineering serotype AAVPHP.eB with enhanced BBB crossing ability further expanded clade F AAVs' usages in the murine central nervous system (CNS) gene delivery. In this study, we determined the cryo-electron microscopy (cryo-EM) structures of the AAVPHP.eB and its parental serotype AAV9 in native form or in complex with their essential receptor AAV receptor (AAVR). These structures reveal the molecular details of their AAVR recognition, where the polycystic kidney disease repeat domain 2 (PKD2) of AAVR interacts with AAV9 and AAVPHP.eB virions at the 3-fold protrusions and the raised capsid regions between the 2- and 5-fold axes, termed the 2/5-fold wall. The interacting patterns of AAVR to AAV9 and AAVPHP.eB are similar to what was observed in AAV1/AAV2-AAVR complexes. Moreover, we found that the AAVPHP.eB variable region VIII (VR-VIII) may independently facilitate the new receptor recognition responsible for enhanced CNS transduction. Our study provides insights into the recognition principles of multiple receptors for engineered AAVPHP.eB and parental serotype AAV9, and further reveal the potential molecular basis underlying their different tropisms.
External linksMol Ther Methods Clin Dev / PubMed:35755945 / PubMed Central
MethodsEM (single particle)
Resolution2.85 - 3.87 Å
Structure data

32550

7wjw

EMDB-32550, PDB-7wjw:
Structure of Adeno-associated virus serotype 9
Method: EM (single particle) / Resolution: 3.87 Å

32551

7wjx

EMDB-32551, PDB-7wjx:
Adeno-associated virus serotype 9 in complex with AAVR
Method: EM (single particle) / Resolution: 3.23 Å

32711

7wqo

EMDB-32711, PDB-7wqo:
Structure of Adeno-associated virus serotype PHP.eB
Method: EM (single particle) / Resolution: 2.85 Å

32712

7wqp

EMDB-32712, PDB-7wqp:
Adeno-associated virus serotype PHP.eB in complex with AAVR
Method: EM (single particle) / Resolution: 3.76 Å

Source
  • adeno-associated virus 9
  • homo sapiens (human)
KeywordsVIRUS / Adeno-associated virus / Adeno-associated virus serotype 9 / AAVR

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