Structures of the Staphylococcus aureus ribosome inhibited by fusidic acid and fusidic acid cyclopentane

被引:1
|
作者
Gonzalez-Lopez, Adrian [1 ]
Larsson, Daniel S. D. [1 ]
Koripella, Ravi Kiran [1 ,3 ]
Cain, Brett N. [2 ]
Chavez, Martin Garcia [2 ]
Hergenrother, Paul J. [2 ]
Sanyal, Suparna [1 ]
Selmer, Maria [1 ]
机构
[1] Uppsala Univ, Dept Cell & Mol Biol, BMC, POB 596, S-75124 Uppsala, Sweden
[2] Univ Illinois, Dept Chem, Urbana, IL 61801 USA
[3] Emory Univ, Robert P Apkarian Integrated Electron Microscopy C, Atlanta, GA USA
来源
SCIENTIFIC REPORTS | 2024年 / 14卷 / 01期
基金
瑞典研究理事会;
关键词
Fusidic acid; Ribosome; EF-G; Cryo-EM; Elongation factor G; ELONGATION-FACTOR-G; TRANSFER-RNA; EF-G; RECYCLING FACTOR; MOLECULAR-BASIS; RESISTANCE; TRANSLOCATION; MECHANISM; COMPLEX; RRF;
D O I
10.1038/s41598-024-64868-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The antibiotic fusidic acid (FA) is used to treat Staphylococcus aureus infections. It inhibits protein synthesis by binding to elongation factor G (EF-G) and preventing its release from the ribosome after translocation. While FA, due to permeability issues, is only effective against gram-positive bacteria, the available structures of FA-inhibited complexes are from gram-negative model organisms. To fill this knowledge gap, we solved cryo-EM structures of the S. aureus ribosome in complex with mRNA, tRNA, EF-G and FA to 2.5 & Aring; resolution and the corresponding complex structures with the recently developed FA derivative FA-cyclopentane (FA-CP) to 2.0 & Aring; resolution. With both FA variants, the majority of the ribosomal particles are observed in chimeric state and only a minor population in post-translocational state. As expected, FA binds in a pocket between domains I, II and III of EF-G and the sarcin-ricin loop of 23S rRNA. FA-CP binds in an identical position, but its cyclopentane moiety provides additional contacts to EF-G and 23S rRNA, suggesting that its improved resistance profile towards mutations in EF-G is due to higher-affinity binding. These high-resolution structures reveal new details about the S. aureus ribosome, including confirmation of many rRNA modifications, and provide an optimal starting point for future structure-based drug discovery on an important clinical drug target.
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页数:13
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