P20A inhibits HIV-1 fusion through its electrostatic interaction with the distal region of the gp41 fusion core

Microbes Infect. 2015 Sep;17(9):665-70. doi: 10.1016/j.micinf.2015.05.003. Epub 2015 May 21.

Abstract

We previously identified an HIV-1 fusion inhibitor P20A targeting HIV-1 gp41 6-HB fusion core. Using alanine scanning mutagenesis, we investigated the effect of 6-HB surface residue mutations on the binding affinity between P20A and 6-HB. Substitution of positively or negatively charged residues in the distal region of 6-HB with alanines resulted in significant decrease or increase of its binding affinity to P20A, respectively. The 6-HB with E630K, D632K, or E634K mutation exhibited enhanced binding affinity with P20A, suggesting that P20A blocks HIV-1 fusion through electrostatic interaction with the positively charged residues in the distal region of the gp41 fusion core.

Keywords: Alanine scanning mutagenesis; HIV-1; Six-helix bundle; gp41 Fusion core.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • HIV Envelope Protein gp41 / chemistry*
  • HIV Envelope Protein gp41 / genetics
  • HIV Envelope Protein gp41 / metabolism*
  • HIV Fusion Inhibitors / chemistry*
  • HIV Fusion Inhibitors / metabolism*
  • HIV-1 / genetics
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Sequence Alignment
  • Static Electricity
  • Virus Internalization

Substances

  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors