title: X-ray crystallographic study of an HIV-1 fusion inhibitor with the gp41 S138A substitution.
abstract: 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.
authors.affiliation: Kyoto University, Sakyo-ku, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watabe
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Terakawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nakano
authors.forename: Toru
authors.initials: T
authors.lastname: Nakatsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kato
authors.forename: Kazuki
authors.initials: K
authors.lastname: Izumi
authors.forename: Eiichi
authors.initials: E
authors.lastname: Kodama
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitaura
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides