Structure of antibody F425-B4e8 in complex with a V3 peptide reveals a new binding mode for HIV-1 neutralization

J Mol Biol. 2008 Jan 25;375(4):969-78. doi: 10.1016/j.jmb.2007.11.013. Epub 2007 Nov 13.

Abstract

F425-B4e8 (B4e8) is a monoclonal antibody isolated from a human immunodeficiency virus type 1 (HIV-1)-infected individual that recognizes the V3 variable loop on the gp120 subunit of the viral envelope spike. B4e8 neutralizes a subset of HIV-1 primary isolates from subtypes B, C and D, which places this antibody among the very few human anti-V3 antibodies with notable cross-neutralizing activity. Here, the crystal structure of the B4e8 Fab' fragment in complex with a 24-mer V3 peptide (RP142) at 2.8 A resolution is described. The complex structure reveals that the antibody recognizes a novel V3 loop conformation, featuring a five-residue alpha-turn around the conserved GPGRA apex of the beta-hairpin loop. In agreement with previous mutagenesis analyses, the Fab' interacts primarily with V3 through side-chain contacts with just two residues, Ile(P309) and Arg(P315), while the remaining contacts are to the main chain. The structure helps explain how B4e8 can tolerate a certain degree of sequence variation within V3 and, hence, is able to neutralize an appreciable number of different HIV-1 isolates.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal / metabolism
  • Asparagine / metabolism
  • Computer Simulation
  • Cross Reactions / immunology
  • Crystallography, X-Ray
  • Glycosylation
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / immunology
  • HIV-1 / chemistry*
  • HIV-1 / immunology
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / isolation & purification
  • Immunoglobulin Fab Fragments / metabolism*
  • Models, Chemical
  • Models, Molecular
  • Neutralization Tests
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism*
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Synchrotrons

Substances

  • Antibodies, Monoclonal
  • HIV Envelope Protein gp120
  • Immunoglobulin Fab Fragments
  • Peptide Fragments
  • Asparagine

Associated data

  • PDB/2QSC