当前位置: X-MOL 学术Viruses › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
The Structure of an AAV5-AAVR Complex at 2.5 Å Resolution: Implications for Cellular Entry and Immune Neutralization of AAV Gene Therapy Vectors
Viruses ( IF 3.8 ) Pub Date : 2020-11-18 , DOI: 10.3390/v12111326
Mark A Silveria 1 , Edward E Large 1 , Grant M Zane 1 , Tommi A White 1, 2 , Michael S Chapman 1
Affiliation  

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.

中文翻译:


2.5 Å 分辨率下 AAV5-AAVR 复合物的结构:对 AAV 基因治疗载体的细胞进入和免疫中和的影响



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疗法的载体,但其生物学特性仍未完全了解。研究表明,不同血清型的 AAV 以不同的方式与其细胞受体 AAVR 结合。此前,我们报道了 AAV2 与 AAVR 结合的 2.4Å 结构,该结构仅显示与 AAV2 相互作用的两个 AAVR 结构域之一的有序结构。在这项研究中,我们展示了 AAV5 与 AAVR 结合的 2.5Å 分辨率结构。 AAV5 与 AAVR 的第一个多囊肾病 (PKD) 结构域结合,该结构域在 AAV2 结构中未排序。详细分析了 AAV5 与 AAVR 的相互作用,并通过分子建模探讨了 AAV2 结合的影响。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药物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。
更新日期:2020-11-18
down
wechat
bug