Oroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.

Alpha-hemolysin (α-HL) is a self-assembling, channel-forming toxin produced by most Staphylococcus aureus strains as a 33.2-kDa soluble monomer. Upon binding to a susceptible cell membrane, the monomer self-assembles to form a 232.4-kDa heptamer that ultimately causes host cell lysis and death. Cons...

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Autores principales:	Jing Dong, Jiazhang Qiu, Yu Zhang, Chongjian Lu, Xiaohan Dai, Jianfeng Wang, Hongen Li, Xin Wang, Wei Tan, Mingjing Luo, Xiaodi Niu, Xuming Deng
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e28b4c05ccfb46f18766ecfc2ffe0a3e
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spelling	oai:doaj.org-article:e28b4c05ccfb46f18766ecfc2ffe0a3e2021-11-18T05:52:30ZOroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.1553-734X1553-735810.1371/journal.pcbi.1002869https://doaj.org/article/e28b4c05ccfb46f18766ecfc2ffe0a3e2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23349625/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Alpha-hemolysin (α-HL) is a self-assembling, channel-forming toxin produced by most Staphylococcus aureus strains as a 33.2-kDa soluble monomer. Upon binding to a susceptible cell membrane, the monomer self-assembles to form a 232.4-kDa heptamer that ultimately causes host cell lysis and death. Consequently, α-HL plays a significant role in the pathogenesis of S. aureus infections, such as pneumonia, mastitis, keratitis and arthritis. In this paper, experimental studies show that oroxylin A (ORO), a natural compound without anti-S. aureus activity, can inhibit the hemolytic activity of α-HL. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were performed to understand the formation of the α-HL-ORO complex. This combined approach revealed that the catalytic mechanism of inhibition involves the direct binding of ORO to α-HL, which blocks the conformational transition of the critical "Loop" region of the α-HL protein thereby inhibiting its hemolytic activity. This mechanism was confirmed by experimental data obtained from a deoxycholate-induced oligomerization assay. It was also found that, in a co-culture system with S. aureus and human alveolar epithelial (A549) cells, ORO could protect against α-HL-mediated injury. These findings indicate that ORO hinders the lytic activity of α-HL through a novel mechanism, which should facilitate the design of new and more effective antibacterial agents against S. aureus.Jing DongJiazhang QiuYu ZhangChongjian LuXiaohan DaiJianfeng WangHongen LiXin WangWei TanMingjing LuoXiaodi NiuXuming DengPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 9, Iss 1, p e1002869 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Jing Dong Jiazhang Qiu Yu Zhang Chongjian Lu Xiaohan Dai Jianfeng Wang Hongen Li Xin Wang Wei Tan Mingjing Luo Xiaodi Niu Xuming Deng Oroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.
description	Alpha-hemolysin (α-HL) is a self-assembling, channel-forming toxin produced by most Staphylococcus aureus strains as a 33.2-kDa soluble monomer. Upon binding to a susceptible cell membrane, the monomer self-assembles to form a 232.4-kDa heptamer that ultimately causes host cell lysis and death. Consequently, α-HL plays a significant role in the pathogenesis of S. aureus infections, such as pneumonia, mastitis, keratitis and arthritis. In this paper, experimental studies show that oroxylin A (ORO), a natural compound without anti-S. aureus activity, can inhibit the hemolytic activity of α-HL. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were performed to understand the formation of the α-HL-ORO complex. This combined approach revealed that the catalytic mechanism of inhibition involves the direct binding of ORO to α-HL, which blocks the conformational transition of the critical "Loop" region of the α-HL protein thereby inhibiting its hemolytic activity. This mechanism was confirmed by experimental data obtained from a deoxycholate-induced oligomerization assay. It was also found that, in a co-culture system with S. aureus and human alveolar epithelial (A549) cells, ORO could protect against α-HL-mediated injury. These findings indicate that ORO hinders the lytic activity of α-HL through a novel mechanism, which should facilitate the design of new and more effective antibacterial agents against S. aureus.
format	article
author	Jing Dong Jiazhang Qiu Yu Zhang Chongjian Lu Xiaohan Dai Jianfeng Wang Hongen Li Xin Wang Wei Tan Mingjing Luo Xiaodi Niu Xuming Deng
author_facet	Jing Dong Jiazhang Qiu Yu Zhang Chongjian Lu Xiaohan Dai Jianfeng Wang Hongen Li Xin Wang Wei Tan Mingjing Luo Xiaodi Niu Xuming Deng
author_sort	Jing Dong
title	Oroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.
title_short	Oroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.
title_full	Oroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.
title_fullStr	Oroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.
title_full_unstemmed	Oroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.
title_sort	oroxylin a inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/e28b4c05ccfb46f18766ecfc2ffe0a3e
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Oroxylin A inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore.

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