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TitleDynamic HIV-1 spike motion creates vulnerability for its membrane-bound tripod to antibody attack.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 6393, Year 2022
Publish dateOct 27, 2022
AuthorsShuang Yang / Giorgos Hiotis / Yi Wang / Junjian Chen / Jia-Huai Wang / Mikyung Kim / Ellis L Reinherz / Thomas Walz /
PubMed AbstractVaccines targeting HIV-1's gp160 spike protein are stymied by high viral mutation rates and structural chicanery. gp160's membrane-proximal external region (MPER) is the target of naturally arising ...Vaccines targeting HIV-1's gp160 spike protein are stymied by high viral mutation rates and structural chicanery. gp160's membrane-proximal external region (MPER) is the target of naturally arising broadly neutralizing antibodies (bnAbs), yet MPER-based vaccines fail to generate bnAbs. Here, nanodisc-embedded spike protein was investigated by cryo-electron microscopy and molecular-dynamics simulations, revealing spontaneous ectodomain tilting that creates vulnerability for HIV-1. While each MPER protomer radiates centrally towards the three-fold axis contributing to a membrane-associated tripod structure that is occluded in the upright spike, tilting provides access to the opposing MPER. Structures of spike proteins with bound 4E10 bnAb Fabs reveal that the antibody binds exposed MPER, thereby altering MPER dynamics, modifying average ectodomain tilt, and imposing strain on the viral membrane and the spike's transmembrane segments, resulting in the abrogation of membrane fusion and informing future vaccine development.
External linksNat Commun / PubMed:36302771 / PubMed Central
MethodsEM (single particle)
Resolution3.67 - 8.79 Å
Structure data

25022

7sc5

EMDB-25022, PDB-7sc5:
Cytoplasmic tail deleted HIV Env trimer in nanodisc
Method: EM (single particle) / Resolution: 3.88 Å

EMDB-25024: Cryo-EM map for HIV-1 Env bound with one 4E10 Fab
Method: EM (single particle) / Resolution: 8.79 Å

EMDB-25025: Cryo-EM map for HIV-1 Env bound with two 4E10 Fabs
Method: EM (single particle) / Resolution: 8.24 Å

25045

7sd3

EMDB-25045, PDB-7sd3:
Cytoplasmic tail deleted HIV-1 Env bound with three 4E10 Fabs
Method: EM (single particle) / Resolution: 3.67 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • hiv whole-genome vector aa1305#18 (others)
  • homo sapiens (human)
KeywordsVIRAL PROTEIN / HIV / Spike / trimer / nanodisc / VIRAL PROTEIN/IMMUNE SYSTEM / envelope / fab / VIRAL PROTEIN-IMMUNE SYSTEM complex

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