Structure of an HIV-1-neutralizing antibody target, the lipid-bound gp41 envelope membrane proximal region trimer

Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1391-6. doi: 10.1073/pnas.1309842111. Epub 2014 Jan 13.

Abstract

The membrane proximal external region (MPER) of HIV-1 glycoprotein (gp) 41 is involved in viral-host cell membrane fusion. It contains short amino acid sequences that are binding sites for the HIV-1 broadly neutralizing antibodies 2F5, 4E10, and 10E8, making these binding sites important targets for HIV-1 vaccine development. We report a high-resolution structure of a designed MPER trimer assembled on a detergent micelle. The NMR solution structure of this trimeric domain, designated gp41-M-MAT, shows that the three MPER peptides each adopt symmetric α-helical conformations exposing the amino acid side chains of the antibody binding sites. The helices are closely associated at their N termini, bend between the 2F5 and 4E10 epitopes, and gradually separate toward the C termini, where they associate with the membrane. The mAbs 2F5 and 4E10 bind gp41-M-MAT with nanomolar affinities, consistent with the substantial exposure of their respective epitopes in the trimer structure. The traditional structure determination of gp41-M-MAT using the Xplor-NIH protocol was validated by independently determining the structure using the DISCO sparse-data protocol, which exploits geometric arrangement algorithms that guarantee to compute all structures and assignments that satisfy the data.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Biopolymers / chemistry
  • Biopolymers / immunology*
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / immunology*
  • HIV-1 / immunology*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Sequence Data

Substances

  • Antibodies, Neutralizing
  • Biopolymers
  • HIV Envelope Protein gp41

Associated data

  • PDB/2LP7
  • PDB/2M7W