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-Structure paper
| タイトル | Adeno-Associated Virus Receptor-Binding: Flexible Domains and Alternative Conformations through Cryo-Electron Tomography of Adeno-Associated Virus 2 (AAV2) and AAV5 Complexes. |
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| ジャーナル・号・ページ | J Virol, Vol. 96, Issue 13, Page e0010622, Year 2022 |
| 掲載日 | 2022年7月13日 |
 著者 | Guiqing Hu / Mark A Silveria / Grant M Zane / Michael S Chapman / Scott M Stagg /  |
| PubMed 要旨 | Recombinant forms of adeno-associated virus (rAAV) are vectors of choice in the development of treatments for a number of genetic dispositions. Greater understanding of AAV's molecular virology is ...Recombinant forms of adeno-associated virus (rAAV) are vectors of choice in the development of treatments for a number of genetic dispositions. Greater understanding of AAV's molecular virology is needed to underpin needed improvements in efficiency and specificity. Recent advances have included identification of a near-universal entry receptor, AAVR, and structures detected by cryo-electron microscopy (EM) single particle analysis (SPA) that revealed, at high resolution, only the domains of AAVR most tightly bound to AAV. Here, cryogenic electron tomography (cryo-ET) is applied to reveal the neighboring domains of the flexible receptor. For AAV5, where the PKD1 domain is bound strongly, PKD2 is seen in three configurations extending away from the virus. AAV2 binds tightly to the PKD2 domain at a distinct site, and cryo-ET now reveals four configurations of PKD1, all different from that seen in AAV5. The AAV2 receptor complex also shows unmodeled features on the inner surface that appear to be an equilibrium alternate configuration. Other AAV structures start near the 5-fold axis, but now β-strand A is the minor conformer and, for the major conformer, partially ordered N termini near the 2-fold axis join the canonical capsid jellyroll fold at the βA-βB turn. The addition of cryo-ET is revealing unappreciated complexity that is likely relevant to viral entry and to the development of improved gene therapy vectors. With 150 clinical trials for 30 diseases under way, AAV is a leading gene therapy vector. Immunotoxicity at high doses used to overcome inefficient transduction has occasionally proven fatal and highlighted gaps in fundamental virology. AAV enters cells, interacting through distinct sites with different domains of the AAVR receptor, according to AAV clade. Single domains are resolved in structures by cryogenic electron microscopy. Here, the adjoining domains are revealed by cryo-electron tomography of AAV2 and AAV5 complexes. They are in flexible configurations interacting minimally with AAV, despite measurable dependence of AAV2 transduction on both domains. |
 リンク | J Virol / PubMed:35674430 / PubMed Central |
| 手法 | EM (サブトモグラム平均) / EM (単粒子) |
| 解像度 | 2.88 - 25.0 Å |
| 構造データ |  EMDB-26172: Global average of aligned subtomograms of AAV2 bound with PKD1-2  EMDB-26173: First class of AAV2 bound with PKD1-2 revealed by classification of aligned subtomgrams  EMDB-26174: Second class of AAV2 bound with PKD1-2 revealed by classification of aligned subtomgrams  EMDB-26175: Third class of AAV2 bound with PKD1-2 revealed by classification of aligned subtomgrams  EMDB-26176: Fourth class of AAV2 bound with PKD1-2 revealed by classification of aligned subtomgrams  EMDB-26177: SPR reconstruction of AAV5 bound with PKD1-2  EMDB-26182: Global average of aligned subtomograms of AAV5 bound with PKD1-2  EMDB-26186: First class of AAV5 bound with PKD1-2 revealed by classification of aligned subtomgrams  EMDB-26187: Second class of AAV5 bound with PKD1-2 revealed by classification of aligned subtomgrams  EMDB-26189: Third class of AAV5 bound with PKD1-2 revealed by classification of aligned subtomograms |
| 由来 |
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Adeno-associated virus - 2 (アデノ随伴ウイルス)
Homo sapiens (ヒト)