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 /
PubMed Abstract
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 ...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.
EMDB-9790, PDB-6jbh: Cryo-EM structure and transport mechanism of a wall teichoic acid ABC transporter Method: EM (single particle) / Resolution: 3.94 Å
Source
alicyclobacillus herbarius (bacteria)
Keywords
TRANSPORT PROTEIN / ABC Transporter
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Keywords
alicyclobacillus herbarius (bacteria)