Structure of engineered hepatitis C virus E1E2 ectodomain in complex with neutralizing antibodies.
Structure of engineered hepatitis C virus E1E2 ectodomain in complex with neutralizing antibodies.
复制标题
DOI：
10.1038/s41467-023-39659-z
复制
发表时间：
2023-07-05
影响因子：
16.6
通讯作者：
Ofek, Gilad
中科院分区：
文献类型：
--
作者：
Metcalf, Matthew C.;Janus, Benjamin M.;Yin, Rui;Wang, Ruixue;Guest, Johnathan D.;Pozharski, Edwin;Law, Mansun;Mariuzza, Roy A.;Toth, Eric A.;Pierce, Brian G.;Fuerst, Thomas R.;Ofek, Gilad
丙型肝炎病毒（HCV）是慢性肝病和肝细胞癌的主要病原体，是全球主要的健康负担。虽然HCV中和抗体的主要抗原靶标是膜相关的E1 E2表面糖蛋白，但有效疫苗的开发受到可溶性E1 E2胞外域的生化制备中的并发症的阻碍。在这里，我们提出了一个冷冻EM结构的基因型1b的工程，分泌E1 E2胞外域与中和抗体AR 4A，HEPC 74，IGH 520的复合物。E2的E1亚基和C-末端区域的结构表征揭示了E1 E2的总体结构，其与非工程化全长E1 E2所观察到的一致。在E2核心和E1之间桥接的E2区域内的AR 4A表位的分析定义了其广泛中和的结构基础。我们的研究提出了通过设计的支架从膜中释放的E1 E2复合物的结构，该支架保持了天然E1 E2的所有基本结构特征。该研究推进了对E1 E2异二聚体结构的理解，这对于疫苗开发中分泌的E1 E2抗原的合理设计至关重要。HCV疫苗的开发一直受到E1 E2胞外域生物化学制备困难的挑战。在这里，作者在结构上表征了与广泛中和抗体复合的工程化可溶性E1 E2胞外域，揭示了它采用了适合疫苗设计的天然折叠。
Hepatitis C virus (HCV) is a major global health burden as the leading causative agent of chronic liver disease and hepatocellular carcinoma. While the main antigenic target for HCV-neutralizing antibodies is the membrane-associated E1E2 surface glycoprotein, the development of effective vaccines has been hindered by complications in the biochemical preparation of soluble E1E2 ectodomains. Here, we present a cryo-EM structure of an engineered, secreted E1E2 ectodomain of genotype 1b in complex with neutralizing antibodies AR4A, HEPC74, and IGH520. Structural characterization of the E1 subunit and C-terminal regions of E2 reveal an overall architecture of E1E2 that concurs with that observed for non-engineered full-length E1E2. Analysis of the AR4A epitope within a region of E2 that bridges between the E2 core and E1 defines the structural basis for its broad neutralization. Our study presents the structure of an E1E2 complex liberated from membrane via a designed scaffold, one that maintains all essential structural features of native E1E2. The study advances the understanding of the E1E2 heterodimer structure, crucial for the rational design of secreted E1E2 antigens in vaccine development. HCV vaccine development has been challenged by difficulties in the biochemical preparation of E1E2 ectodomains. Here, the authors structurally characterize an engineered soluble E1E2 ectodomain complexed with broadly neutralizing antibodies, revealing it adopts a native fold amenable for vaccine design.
登录
查看更多内容
影响因子：
6.7
作者：
Gopal, Radhika;Jackson, Kelli;Law, Mansun
通讯作者：
Law, Mansun
影响因子：
7.6
作者：
Cai, Weijia;Su, Liya;She, Yinglong
通讯作者：
She, Yinglong
影响因子：
16.6
作者：
El Omari, Kamel;Iourin, Oleg;Kadlec, Jan;Sutton, Geoff;Harlos, Karl;Grimes, Jonathan M.;Stuart, David I.
通讯作者：
Stuart, David I.
影响因子：
8
作者：
Bailey, Justin R.;Flyak, Andrew I.;Crowe, James E., Jr.
通讯作者：
Crowe, James E., Jr.
影响因子：
5.4
作者：
Falson, Pierre;Bartosch, Birke;Penin, Francois
通讯作者：
Penin, Francois