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| Title | Conformational trajectory of the HIV-1 fusion peptide during CD4-induced envelope opening. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 16, Issue 1, Page 4595, Year 2025 |
| Publish date | May 17, 2025 |
 Authors | Bhishem Thakur / Revansiddha H Katte / Wang Xu / Katarzyna Janowska / Salam Sammour / Rory Henderson / Maolin Lu / Peter D Kwong / Priyamvada Acharya /  |
| PubMed Abstract | The hydrophobic fusion peptide (FP), a critical component of the HIV-1 entry machinery, is located at the N terminus of the envelope (Env) gp41 subunit. The receptor-binding gp120 subunit of Env ...The hydrophobic fusion peptide (FP), a critical component of the HIV-1 entry machinery, is located at the N terminus of the envelope (Env) gp41 subunit. The receptor-binding gp120 subunit of Env forms a heterodimer with gp41. The gp120/gp41 heterodimer assembles into a homotrimer, in which FP is accessible for antibody binding. Env conformational changes or "opening" that follow receptor binding result in FP relocating to a newly formed interprotomer pocket at the gp41-gp120 interface where it is sterically inaccessible to antibodies. The mechanistic steps connecting the entry-related transition of antibody accessible-to-inaccessible FP configurations remain unresolved. Here, using SOSIP-stabilized Env ectodomains, we visualize that the FP remains accessible for antibody binding despite substantial receptor-induced Env opening. We delineate stepwise Env opening from its closed state to a functional CD4-bound symmetrically open Env in which we show that FP was accessible for antibody binding. We define downstream re-organizations that lead to the formation of a gp120/gp41 cavity into which the FP buries to become inaccessible for antibody binding. These findings improve our understanding of HIV-1 entry and delineate the entry-related conformational trajectory of a key site of HIV vulnerability to neutralizing antibody. |
 External links | Nat Commun / PubMed:40382314 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.91 - 6.4 Å |
| Structure data | EMDB-46653, PDB-9d8y: EMDB-46655, PDB-9d90: EMDB-46670, PDB-9d98:  EMDB-46671: Cryo-EM structure of partially open HIV-1 BG505 SOSIP.664 Env bound to 3-sCD4, 3-17b Fab and 2-VRC34.01 Fab. Population 2  EMDB-46672: Cryo-EM structure of partially open HIV-1 BG505 SOSIP.664 Env bound to 3-sCD4, 3-17b Fab and 1-VRC34.01 Fab, Population 3 |
| Chemicals |  ChemComp-NAG: |
| Source |
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 Keywords | VIRAL PROTEIN/IMMUNE SYSTEM / Recombinant protein / HIV-1 Env / CD4 / fusion peptide binning antibody VRC34.01 / Vaccine / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / Recombinantly purified HIV-1 Env / sCD4 / 17b Fab and VRC34.01 Fab / viral Env |
human immunodeficiency virus 1
homo sapiens (human)