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

• Published in: mBio 2020-03, Vol.11 (2)
• Main Authors: Chen, Li, Hou, Wen-Tao, Fan, Tao, Liu, Banghui, Pan, Ting, Li, Yu-Hui, Jiang, Yong-Liang, Wen, Wen, Chen, Zhi-Peng, Sun, Linfeng, Zhou, Cong-Zhao, Chen, Yuxing
• Format: Article
• Language: English
• Subjects: ABC transporters; Alicyclobacillus - chemistry; Alicyclobacillus - genetics; Anti-Bacterial Agents - pharmacology; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette Transporters - ultrastructure; Cell Wall - chemistry; Cell Wall - ultrastructure; cryo-EM; Cryoelectron Microscopy; inhibitors; Methicillin-Resistant Staphylococcus aureus - chemistry; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - genetics; Molecular Biology and Physiology; MRSA; Protein Binding; Staphylococcus aureus; Teichoic Acids - chemistry; wall teichoic acids
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mbio.02749-19

The wall teichoic acid (WTA) is a major cell wall component of Gram-positive bacteria, such as methicillin-resistant (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 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. The wall teichoic acid (WTA) is a major component of cell wall and a pathogenic factor in methicillin-resistant (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.