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TitleDesign of soluble HIV-1 envelope trimers free of covalent gp120-gp41 bonds with prevalent native-like conformation.
Journal, issue, pagesCell Rep, Vol. 43, Issue 8, Page 114518, Year 2024
Publish dateJul 18, 2024
AuthorsPeng Zhang / Jason Gorman / Yaroslav Tsybovsky / Maolin Lu / Qingbo Liu / Vinay Gopan / Mamta Singh / Yin Lin / Huiyi Miao / Yuna Seo / Alice Kwon / Adam S Olia / Gwo-Yu Chuang / Hui Geng / Yen-Ting Lai / Tongqing Zhou / John R Mascola / Walther Mothes / Peter D Kwong / Paolo Lusso /
PubMed AbstractSoluble HIV-1 envelope (Env) trimers may serve as effective vaccine immunogens. The widely utilized SOSIP trimers have been paramount for structural studies, but the disulfide bond they feature ...Soluble HIV-1 envelope (Env) trimers may serve as effective vaccine immunogens. The widely utilized SOSIP trimers have been paramount for structural studies, but the disulfide bond they feature between gp120 and gp41 constrains intersubunit mobility and may alter antigenicity. Here, we report an alternative strategy to generate stabilized soluble Env trimers free of covalent gp120-gp41 bonds. Stabilization was achieved by introducing an intrasubunit disulfide bond between the inner and outer domains of gp120, defined as interdomain lock (IDL). Correctly folded IDL trimers displaying a native-like antigenic profile were produced for HIV-1 Envs of different clades. Importantly, the IDL design abrogated CD4 binding while not affecting recognition by potent neutralizing antibodies to the CD4-binding site. By cryoelectron microscopy, IDL trimers were shown to adopt a closed prefusion configuration, while single-molecule fluorescence resonance energy transfer documented a high prevalence of native-like conformation. Thus, IDL trimers may be promising candidates as vaccine immunogens.
External linksCell Rep / PubMed:39028623
MethodsEM (single particle)
Resolution3.3 - 4.5 Å
Structure data

44482

9ber

EMDB-44482, PDB-9ber:
Cryo-EM structure of the HIV-1 JR-FL IDL Env trimer in complex with PGT122 Fab
Method: EM (single particle) / Resolution: 4.1 Å

44484

9bew

EMDB-44484, PDB-9bew:
Cryo-EM structure of the HIV-1 BG505 IDL Env trimer in complex with 3BNC117 and 10-1074 Fabs
Method: EM (single particle) / Resolution: 3.3 Å

44491

9bf6

EMDB-44491, PDB-9bf6:
Cryo-EM structure of the HIV-1 WITO IDL Env trimer in complex with PGT122 Fab
Method: EM (single particle) / Resolution: 4.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-SO4:
SULFATE ION

ChemComp-PO4:
PHOSPHATE ION

Source
  • human immunodeficiency virus 1
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / CD4 / HIV-1 / SOSIP / Vaccine / gp120 / gp41 / VIRAL PROTEIN-IMMUNE SYSTEM complex

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