X-ray crystallographic study of an HIV-1 fusion inhibitor with the gp41 S138A substitution.
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.
Watabe
Tsuyoshi
T
Kyoto University, Sakyo-ku, Japan.
Terakawa
Yukihiro
Y
Watanabe
Kentaro
K
Ohno
Hiroaki
H
Nakano
Hiroaki
H
Nakatsu
Toru
T
Kato
Hiroaki
H
Izumi
Kazuki
K
Kodama
Eiichi
E
Matsuoka
Masao
M
Kitaura
Kazuo
K
Oishi
Shinya
S
Fujii
Nobutaka
N
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
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides