期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29274-9
关键词
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资金
- Knut and Alice Wallenberg Foundation
- Family Erling Persson Foundation
- Kempe Foundation
- SciLifeLab
- Stockholm University
- Umea University
- Deutsche Forschungsgemeinschaft (DFG) [WI3285/8-1]
- Swedish Research Council (Vetenskapsradet) grants [2017-03783, 2021-01146, 2019-01085]
- Ragnar Soderbergs Stiftelse
- Umea Centre for Microbial Research, UCMR
- European Union from the European Regional Development Fund through the Centre of Excellence in Molecular Cell Engineering [2014-2020.4.01.15-0013]
- Estonian Research Council [PRG335]
- Deutsche Zentrum fur Luft-und Raumfahrt [DLR01Kl1820]
- Swedish Research Council within the RIBOTARGET consortium [2018-00956]
- Knut and AliceWallenberg Foundation [2020-0037]
- Swedish Foundation's Starting Grant (Ragnar Soderberg Foundation)
- Swedish Research Council [VR 2016-01842, 2020-01480, 2021-06112]
- Wallenberg Academy Fellowship [KAW2016.0123]
- Vinnova [2020-03620]
- Karolinska Institutet (SciLifeLab Fellowship)
- EU H2020MSCA-IF-2018 program [845495 -TERMINATOR]
- Karolinska Institutet (SFO)
- Karolinska Institutet (KI funds)
- Swedish Research Council [2021-01146, 2021-06112, 2018-00956, 2020-01480] Funding Source: Swedish Research Council
- Forte [2020-01480] Funding Source: Forte
- Vinnova [2019-01085, 2020-01480] Funding Source: Vinnova
PoxtA and OptrA are ABC proteins of the F subtype that confer resistance to oxazolidinone and phenicol antibiotics. In this study, the researchers provide structural insights into how PoxtA binding to the ribosome indirectly promotes drug dissociation.
PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by similar to 4 angstrom out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site. PoxtA confers resistance to ribosome-targeting oxazolidinone (linezolid) and chloramphenicol antibiotics. Here, Crowe-McAuliffe et al. provide structural insights into how binding of PoxtA to the ribosome indirectly promotes drug dissociation.
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