Qi Yi, Zhang Shijian, Wang Kunyu, Ding Haitao, Zhang Zhiqing, Anang Saumya, Nguyen Hanh T, Kappes John C, Sodroski Joseph, Mao Youdong
Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Commun Biol. 2025 Mar 15;8(1):442. doi: 10.1038/s42003-025-07852-z.
During human immunodeficiency virus (HIV-1) entry, the metastable pretriggered envelope glycoprotein (Env) trimer ((gp120/gp41)) opens asymmetrically. We present cryo-EM structures of cleaved asymmetric Env trimers in amphipol-lipid nanodiscs. The gp41 membrane-proximal external region (MPER) could be traced in Env protomers that remained close to the nanodisc despite Env tilting. The MPER interacts with the gp120 C-termini and gp41 α9 helices at the base of the Env trimer. MPER conformation is coupled with the tilt angles of the α9 helices, the helicity of the gp41 heptad repeat (HR1) regions, and the opening angles between the protomers of the asymmetric trimers. Our structural models explain the stabilizing effects of MPER integrity and Env proteolytic maturation on the pretriggered Env conformation. Superimposed on the asymmetry of the Env protomers, variation in the glycans at the trimer apex creates substantial structural heterogeneity in the V2 quaternary epitopes of difficult-to-elicit broadly neutralizing antibodies.
在人类免疫缺陷病毒1型（HIV-1）进入过程中，亚稳态的预触发包膜糖蛋白（Env）三聚体（（gp120/gp41））会不对称地打开。我们展示了在两性离子脂质纳米盘中裂解的不对称Env三聚体的冷冻电镜结构。尽管Env发生倾斜，但在仍靠近纳米盘的Env原聚体中可以追踪到gp41膜近端外部区域（MPER）。MPER在Env三聚体的底部与gp120 C末端和gp41 α9螺旋相互作用。MPER构象与α9螺旋的倾斜角度、gp41七肽重复序列（HR1）区域的螺旋度以及不对称三聚体原聚体之间的开口角度相关联。我们的结构模型解释了MPER完整性和Env蛋白水解成熟对预触发Env构象的稳定作用。叠加在Env原聚体的不对称性上，三聚体顶端聚糖的变化在难以诱导产生的广泛中和抗体的V2四级表位中产生了大量的结构异质性。
