Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Nat Commun. 2019 Feb 15;10(1):763. doi: 10.1038/s41467-019-08738-5.
The N-terminal fusion peptide (FP) of the human immunodeficiency virus (HIV)-1 envelope glycoprotein (Env) gp41 subunit plays a critical role in cell entry. However, capturing the structural flexibility in the unbound FP is challenging in the native Env trimer. Here, FP conformational isomerism is observed in two crystal structures of a soluble clade B transmitted/founder virus B41 SOSIP.664 Env with broadly neutralizing antibodies (bNAbs) PGT124 and 35O22 to aid in crystallization and that are not specific for binding to the FP. Large rearrangements in the FP and fusion peptide proximal region occur around M530, which remains anchored in the tryptophan clasp (gp41 W623, W628, W631) in the B41 Env prefusion state. Further, we redesigned the FP at position 518 to reinstate the bNAb VRC34.01 epitope. These findings provide further structural evidence for the dynamic nature of the FP and how a bNAb epitope can be restored during vaccine design.
人类免疫缺陷病毒 (HIV)-1 包膜糖蛋白 (Env) gp41 亚基的 N 端融合肽 (FP) 在细胞进入中起着关键作用。然而，在天然 Env 三聚体中捕捉未结合 FP 的结构灵活性具有挑战性。在这里，观察到两种具有广泛中和抗体 (bNAb) PGT124 和 35O22 的可溶性 B 群传播/原始病毒 B41 SOSIP.664 Env 的 FP 构象异构，这两种抗体有助于结晶，而不是特异性结合 FP。FP 和融合肽近端区域的大重排发生在 M530 周围，在 B41Env 预融合状态下，M530 仍然固定在色氨酸扣 (gp41 W623、W628、W631) 中。此外，我们重新设计了 FP 位置 518 以恢复 bNAb VRC34.01 表位。这些发现为 FP 的动态性质以及在疫苗设计过程中如何恢复 bNAb 表位提供了进一步的结构证据。
