Structure of the membrane proximal external region of HIV-1 envelope glycoprotein

Qingshan Fu1, Md Munan Shaik2,3, Yongfei Cai2,3

  • 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.

Insights

The HIV-1 membrane-proximal external region (MPER) structure reveals a prefusion conformation, offering new insights for developing MPER-based vaccine candidates targeting broadly neutralizing antibodies (bnAbs).

Area of Science:

  • Structural Biology
  • Immunology
  • Virology

Background:

  • The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) is a key target for broadly neutralizing antibodies (bnAbs).
  • Understanding the MPER's structure is crucial for designing effective HIV-1 vaccines.

Purpose of the Study:

  • To determine the NMR structure of the HIV-1 MPER and its adjacent transmembrane domain in a membrane-mimicking environment.
  • To investigate the MPER's conformation and its implications for antibody binding and HIV-1 fusion.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy to determine the MPER structure in bicelles.
  • Antigenic analysis and comparison with electron cryotomography data.

Main Results:

  • The MPER adopts a threefold clustered structure outside the lipid bilayer, stabilized by hydrophobic residues.
  • The determined structure likely represents a prefusion conformation, distinct from the fusion-intermediate state.
  • Slow bnAb binding suggests infrequent structural fluctuations provide access to alternative epitope conformations.

Conclusions:

  • The MPER structure provides a potential prefusion conformation for vaccine design.
  • MPER structure and mutations influence both membrane fusion and the presentation of bnAb epitopes.
  • Findings suggest strategies for developing novel MPER-based HIV-1 vaccine candidates.

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