Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter

ABSTRACT The wall teichoic acid (WTA) is a major cell wall component of Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), a common cause of fatal clinical infections in humans. Thus, the indispensable ABC transporter TarGH, which flips WTA from cytoplasm to extracel...

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Autores principales:	Li Chen, Wen-Tao Hou, Tao Fan, Banghui Liu, Ting Pan, Yu-Hui Li, Yong-Liang Jiang, Wen Wen, Zhi-Peng Chen, Linfeng Sun, Cong-Zhao Zhou, Yuxing Chen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	cryo-EM Staphylococcus aureus inhibitors wall teichoic acids ABC transporters MRSA Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4b2950cd0d604edc9b2a00799d40839d
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spelling	oai:doaj.org-article:4b2950cd0d604edc9b2a00799d40839d2021-11-15T15:57:02ZCryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter10.1128/mBio.02749-192150-7511https://doaj.org/article/4b2950cd0d604edc9b2a00799d40839d2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02749-19https://doaj.org/toc/2150-7511ABSTRACT The wall teichoic acid (WTA) is a major cell wall component of Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), a common cause of fatal clinical infections in humans. Thus, the indispensable ABC transporter TarGH, which flips WTA from cytoplasm to extracellular space, becomes a promising target of anti-MRSA drugs. Here, we report the 3.9-Å cryo-electron microscopy (cryo-EM) structure of a 50% sequence-identical homolog of TarGH from Alicyclobacillus herbarius at an ATP-free and inward-facing conformation. Structural analysis combined with activity assays enables us to clearly decode the binding site and inhibitory mechanism of the anti-MRSA inhibitor Targocil, which targets TarGH. Moreover, we propose a “crankshaft conrod” mechanism utilized by TarGH, which can be applied to similar ABC transporters that translocate a rather big substrate through relatively subtle conformational changes. These findings provide a structural basis for the rational design and optimization of antibiotics against MRSA. IMPORTANCE The wall teichoic acid (WTA) is a major component of cell wall and a pathogenic factor in methicillin-resistant Staphylococcus aureus (MRSA). The ABC transporter TarGH is indispensable for flipping WTA precursor from cytoplasm to the extracellular space, thus making it a promising drug target for anti-MRSA agents. The 3.9-Å cryo-EM structure of a TarGH homolog helps us to decode the binding site and inhibitory mechanism of a recently reported inhibitor, Targocil, and provides a structural platform for rational design and optimization of potential antibiotics. Moreover, we propose a “crankshaft conrod” mechanism to explain how a big substrate is translocated through subtle conformational changes of type II exporters. These findings advance our understanding of anti-MRSA drug design and ABC transporters.Li ChenWen-Tao HouTao FanBanghui LiuTing PanYu-Hui LiYong-Liang JiangWen WenZhi-Peng ChenLinfeng SunCong-Zhao ZhouYuxing ChenAmerican Society for Microbiologyarticlecryo-EMStaphylococcus aureusinhibitorswall teichoic acidsABC transportersMRSAMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	cryo-EM Staphylococcus aureus inhibitors wall teichoic acids ABC transporters MRSA Microbiology QR1-502
spellingShingle	cryo-EM Staphylococcus aureus inhibitors wall teichoic acids ABC transporters MRSA Microbiology QR1-502 Li Chen Wen-Tao Hou Tao Fan Banghui Liu Ting Pan Yu-Hui Li Yong-Liang Jiang Wen Wen Zhi-Peng Chen Linfeng Sun Cong-Zhao Zhou Yuxing Chen Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter
description	ABSTRACT The wall teichoic acid (WTA) is a major cell wall component of Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), a common cause of fatal clinical infections in humans. Thus, the indispensable ABC transporter TarGH, which flips WTA from cytoplasm to extracellular space, becomes a promising target of anti-MRSA drugs. Here, we report the 3.9-Å cryo-electron microscopy (cryo-EM) structure of a 50% sequence-identical homolog of TarGH from Alicyclobacillus herbarius at an ATP-free and inward-facing conformation. Structural analysis combined with activity assays enables us to clearly decode the binding site and inhibitory mechanism of the anti-MRSA inhibitor Targocil, which targets TarGH. Moreover, we propose a “crankshaft conrod” mechanism utilized by TarGH, which can be applied to similar ABC transporters that translocate a rather big substrate through relatively subtle conformational changes. These findings provide a structural basis for the rational design and optimization of antibiotics against MRSA. IMPORTANCE The wall teichoic acid (WTA) is a major component of cell wall and a pathogenic factor in methicillin-resistant Staphylococcus aureus (MRSA). The ABC transporter TarGH is indispensable for flipping WTA precursor from cytoplasm to the extracellular space, thus making it a promising drug target for anti-MRSA agents. The 3.9-Å cryo-EM structure of a TarGH homolog helps us to decode the binding site and inhibitory mechanism of a recently reported inhibitor, Targocil, and provides a structural platform for rational design and optimization of potential antibiotics. Moreover, we propose a “crankshaft conrod” mechanism to explain how a big substrate is translocated through subtle conformational changes of type II exporters. These findings advance our understanding of anti-MRSA drug design and ABC transporters.
format	article
author	Li Chen Wen-Tao Hou Tao Fan Banghui Liu Ting Pan Yu-Hui Li Yong-Liang Jiang Wen Wen Zhi-Peng Chen Linfeng Sun Cong-Zhao Zhou Yuxing Chen
author_facet	Li Chen Wen-Tao Hou Tao Fan Banghui Liu Ting Pan Yu-Hui Li Yong-Liang Jiang Wen Wen Zhi-Peng Chen Linfeng Sun Cong-Zhao Zhou Yuxing Chen
author_sort	Li Chen
title	Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter
title_short	Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter
title_full	Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter
title_fullStr	Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter
title_full_unstemmed	Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter
title_sort	cryo-electron microscopy structure and transport mechanism of a wall teichoic acid abc transporter
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/4b2950cd0d604edc9b2a00799d40839d
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Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter

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