5Z0W

Crystal structure of HIV-1 fusion inhibitor SC29EK complexed with gp41 NHR (N36)

5Z0W の概要

• エントリーDOI: 10.2210/pdb5z0w/pdb
• 分子名称: peptide-N, peptide-C (3 entities in total)
• 機能のキーワード: hiv fusion inhibitor, 6 helix bundle, viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Human immunodeficiency virus 1; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 7873.02

構造登録者

Liu, Z.X.,Qin, B.,Cui, S. (登録日: 2017-12-21, 公開日: 2018-01-10, 最終更新日: 2023-11-22)

主引用文献

Wu, X.,Liu, Z.,Ding, X.,Yu, D.,Wei, H.,Qin, B.,Zhu, Y.,Chong, H.,Cui, S.,He, Y.
Mechanism of HIV-1 Resistance to an Electronically Constrained alpha-Helical Peptide Membrane Fusion Inhibitor
J. Virol., 92:-, 2018

PubMed Abstract: SC29EK is an electronically constrained α-helical peptide HIV-1 fusion inhibitor that is highly effective against both wild-type and enfuvirtide (T20)-resistant viruses. In this study, we focused on investigating the mechanism of HIV-1 resistance to SC29EK by two approaches. First, SC29EK-escaping HIV-1 variants were selected and characterized. Three mutant viruses, which possessed two (N43K/E49A) or three (Q39R/N43K/N126K and N43K/E49A/N126K) amino acid substitutions in the N- and C-terminal repeat regions of gp41 were identified as conferring high resistance to SC29EK and cross-resistance to the first-generation (T20 and C34) and newly designed (sifuvirtide, MT-SC29EK, and 2P23) fusion inhibitors. The resistance mutations could reduce the binding stability of SC29EK, impair viral Env-mediated cell fusion and entry, and change the conformation of the gp41 core structure. Further, we determined the crystal structure of SC29EK in complex with a target mimic peptide, which revealed the critical intra- and interhelical interactions underlying the mode of action of SC29EK and the genetic pathway to HIV-1 resistance. Taken together, the present data provide new insights into the structure and function of gp41 and the structure-activity relationship (SAR) of viral fusion inhibitors. T20 is the only membrane fusion inhibitor available for treatment of viral infection, but it has relatively low anti-HIV activity and genetic barriers for resistance, thus calling for new drugs blocking the viral fusion process. As an electronically constrained α-helical peptide, SC29EK is highly potent against both wild-type and T20-resistant HIV-1 strains. Here, we report the characterization of HIV-1 variants resistant to SC29EK and the crystal structure of SC29EK. The key mutations mediating high resistance to SC29EK and cross-resistance to the first and new generations of fusion inhibitors as well as the underlying mechanisms were identified. The crystal structure of SC29EK bound to a target mimic peptide further revealed its action mode and genetic pathway to inducing resistance. Hence, our data have shed new lights on the mechanisms of HIV-1 fusion and its inhibition.

PubMed: 29321334
DOI: 10.1128/JVI.02044-17

実験手法

X-RAY DIFFRACTION (1.896 Å)