The Structure of an AAV5-AAVR Complex at 2.5 Å Resolution: Implications for Cellular Entry and Immune Neutralization of AAV Gene Therapy Vectors.
The Structure of an AAV5-AAVR Complex at 2.5 Å Resolution: Implications for Cellular Entry and Immune Neutralization of AAV Gene Therapy Vectors.
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DOI：
10.3390/v12111326
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发表时间：
2020-11-18
期刊：
影响因子：
--
通讯作者：
Chapman MS
中科院分区：
文献类型：
--
作者：
Silveria MA;Large EE;Zane GM;White TA;Chapman MS
腺相关病毒是基因治疗的主要载体。尽管它是美国食品和药物管理局批准用于临床的所有体内基因治疗的载体，但其生物学仍未完全了解。已经显示，不同血清型的AAV以不同的方式与它们的细胞受体AAVR结合。先前我们已经报道了与AAVR结合的AAV2的2.4kb结构，其显示了与AAV2相互作用的两个AAVR结构域中仅一个的有序结构。在这项研究中，我们提出了一个2.5 μ m的分辨率结构的AAV5结合到AAVR。AAV5结合AAVR的第一个多囊肾病（PKD）结构域，其在AAV2结构中不有序。详细分析了AAV5与AAVR的相互作用，并通过分子模拟探索了AAV2结合的意义。此外，我们发现AAV5上抗体ADK5a、ADK5b和3C5的结合位点与AAVR的结合位点重叠。这些见解为基因治疗剂的开发提供了结构基础，以更好地逃避免疫中和而不破坏细胞进入。
Adeno-Associated Virus is the leading vector for gene therapy. Although it is the vector for all in vivo gene therapies approved for clinical use by the US Food and Drug Administration, its biology is still not yet fully understood. It has been shown that different serotypes of AAV bind to their cellular receptor, AAVR, in different ways. Previously we have reported a 2.4Å structure of AAV2 bound to AAVR that shows ordered structure for only one of the two AAVR domains with which AAV2 interacts. In this study we present a 2.5Å resolution structure of AAV5 bound to AAVR. AAV5 binds to the first polycystic kidney disease (PKD) domain of AAVR that was not ordered in the AAV2 structure. Interactions of AAV5 with AAVR are analyzed in detail, and the implications for AAV2 binding are explored through molecular modeling. Moreover, we find that binding sites for the antibodies ADK5a, ADK5b, and 3C5 on AAV5 overlap with the binding site of AAVR. These insights provide a structural foundation for development of gene therapy agents to better evade immune neutralization without disrupting cellular entry.
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影响因子：
5.6
作者：
Januliene, Dovile;Manavalan, Arulmani;Moeller, Arne
通讯作者：
Moeller, Arne
影响因子：
7.7
作者：
Meyer, Nancy L.;Hu, Guiqing;Chapman, Michael Stewart
通讯作者：
Chapman, Michael Stewart
影响因子：
5.4
作者：
Govindasamy, Lakshmanan;DiMattia, Michael A.;Agbandje-McKenna, Mavis
通讯作者：
Agbandje-McKenna, Mavis
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
5.4
作者：
Jose, Ariana;Mietzsch, Mario;Agbandje-McKenna, Mavis
通讯作者：
Agbandje-McKenna, Mavis