Oxford Particle Imaging Centre, Department of Structural Biology, Wellcome Centre Human Genetics, University of Oxford, Oxford, UK.
Centre for Structural Systems Biology, Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie, Hamburg, Germany.
Sci Adv. 2020 Sep 25;6(39). doi: 10.1126/sciadv.abc1726. Print 2020 Sep.
Cell entry of enveloped viruses requires specialized viral proteins that mediate fusion with the host membrane by substantial structural rearrangements from a metastable pre- to a stable postfusion conformation. This metastability renders the herpes simplex virus 1 (HSV-1) fusion glycoprotein B (gB) highly unstable such that it readily converts into the postfusion form, thereby precluding structural elucidation of the pharmacologically relevant prefusion conformation. By identification of conserved sequence signatures and molecular dynamics simulations, we devised a mutation that stabilized this form. Functionally locking gB allowed the structural determination of its membrane-embedded prefusion conformation at sub-nanometer resolution and enabled the unambiguous fit of all ectodomains. The resulting pseudo-atomic model reveals a notable conservation of conformational domain rearrangements during fusion between HSV-1 gB and the vesicular stomatitis virus glycoprotein G, despite their very distant phylogeny. In combination with our comparative sequence-structure analysis, these findings suggest common fusogenic domain rearrangements in all class III viral fusion proteins.
包膜病毒的细胞进入需要专门的病毒蛋白，这些蛋白通过从亚稳定的预融合构象到稳定的后融合构象的大量结构重排来介导与宿主膜的融合。这种亚稳定性使单纯疱疹病毒 1（HSV-1）融合糖蛋白 B（gB）极不稳定，容易转化为后融合形式，从而排除了对药理学相关预融合构象的结构阐明。通过鉴定保守序列特征和分子动力学模拟，我们设计了一种突变来稳定这种形式。功能锁定 gB 允许以亚纳米分辨率确定其膜嵌入的预融合构象，并能够明确适合所有的外域。由此产生的拟原子模型揭示了在 HSV-1 gB 与水疱性口炎病毒糖蛋白 G 之间融合过程中构象域重排的显著保守性，尽管它们的系统发育非常遥远。结合我们的比较序列-结构分析，这些发现表明所有 III 类病毒融合蛋白中存在共同的融合域重排。
