X-ray Crystallographic Study of an HIV-1 Fusion Inhibitor with the gp41 S138A Substitution

Tsuyoshi Watabe, Yukihiro Terakawa, Kentaro Watanabe, Hiroaki Ohno, Hiroaki Nakano, Toru Nakatsu, Hiroaki Kato, Kazuki Izumi, Eiichi Kodama, Masao Matsuoka, Kazuo Kitaura, Shinya Oishi, Nobutaka Fujii

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)


The S138A substitution of fusion inhibitory peptides derived from the C-terminal heptad repeat (C-HR) of the human immunodeficiency virus type 1 (HIV-1) gp41 leads to enhanced binding affinity to the N-terminal heptad repeat (N-HR). As such, these peptides exhibit highly potent anti-HIV-1 activity. X-ray crystallographic analysis was performed to understand the effect of the substitution on binding affinity. The comparison of the native and S138A crystal structures indicated that the increase in the hydrophobicity of the S138A substitution may aid the stabilization of the N-HR/C-HR complex through additional hydrophobic contacts. Free-energy calculations suggest that the difference between the desolvation free energies of the C-HR-derived peptides with and without the S138A mutation dominates the observed difference in anti-HIV-1 activity.

Original languageEnglish
Pages (from-to)657-665
Number of pages9
JournalJournal of Molecular Biology
Issue number3
Publication statusPublished - 2009 Sept 25
Externally publishedYes


  • C-HR-derived peptide
  • HIV-1 fusion inhibitor
  • desolvation energy
  • gp41/S138A substitution
  • hydrophobicity

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Molecular Biology


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