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

doi:10.1016/j.jmb.2009.07.027

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 journal › Article › peer-review

15 Citations (Scopus)

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.

Original language	English
Pages (from-to)	657-665
Number of pages	9
Journal	Journal of Molecular Biology
Volume	392
Issue number	3
DOIs	https://doi.org/10.1016/j.jmb.2009.07.027
Publication status	Published - 2009 Sept 25
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Biophysics
Structural Biology
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jmb.2009.07.027

Cite this

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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.",

keywords = "C-HR-derived peptide, HIV-1 fusion inhibitor, desolvation energy, gp41/S138A substitution, hydrophobicity",

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

note = "Funding Information: This work was supported by the Science and Technology Incubation Program in Advanced Regions from Japan Science and Technology Agency; a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and Health and Labour Sciences Research Grants (Research on HIV/AIDS). ",

year = "2009",

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doi = "10.1016/j.jmb.2009.07.027",

language = "English",

volume = "392",

pages = "657--665",

journal = "Journal of Molecular Biology",

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T1 - X-ray Crystallographic Study of an HIV-1 Fusion Inhibitor with the gp41 S138A Substitution

AU - Watabe, Tsuyoshi

AU - Terakawa, Yukihiro

AU - Watanabe, Kentaro

AU - Ohno, Hiroaki

AU - Nakano, Hiroaki

AU - Nakatsu, Toru

AU - Kato, Hiroaki

AU - Izumi, Kazuki

AU - Kodama, Eiichi

AU - Matsuoka, Masao

AU - Kitaura, Kazuo

AU - Oishi, Shinya

AU - Fujii, Nobutaka

N1 - Funding Information: This work was supported by the Science and Technology Incubation Program in Advanced Regions from Japan Science and Technology Agency; a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and Health and Labour Sciences Research Grants (Research on HIV/AIDS).

PY - 2009/9/25

Y1 - 2009/9/25

N2 - 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.

AB - 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.

KW - C-HR-derived peptide

KW - HIV-1 fusion inhibitor

KW - desolvation energy

KW - gp41/S138A substitution

KW - hydrophobicity

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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