期刊
STRUCTURE
卷 20, 期 5, 页码 802-813出版社
CELL PRESS
DOI: 10.1016/j.str.2012.03.013
关键词
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资金
- National Institutes of Health [AI044639, AI070383, T32GM008444, T32GM092714]
- Deutsche Forschungsgemeinschaft [SFB 630, Forschungszentrum FZ82]
- German Excellence Initiative
Methicillin-resistant Staphylococcus aureus (M RSA) infections constitute a serious health threat worldwide, and novel antibiotics are therefore urgently needed. The enoyl-ACP reductase (saFabl) is essential for the S. aureus fatty acid biosynthesis and, hence, serves as an attractive drug target. We have obtained a series of snapshots of this enzyme that provide a mechanistic picture of ligand and inhibitor binding, including a dimer-tetramer transition combined with extensive conformational changes. Significantly, our results reveal key differences in ligand binding and recognition compared to orthologous proteins. The remarkable observed protein flexibility rationalizes our finding that saFabl is capable of efficiently reducing branched-chain fatty acid precursors. Importantly, branched-chain fatty acids represent a major fraction of the S. aureus cell membrane and are crucial for its in vivo fitness. Our discovery thus addresses a long-standing controversy regarding the essentiality of the fatty acid biosynthesis pathway in S. aureus rationalizing saFabl as a drug target.
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