Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-23753-1
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Funding
- 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) [2017-03783, 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]
- Swedish Research Council [2018-00956, 2019-01085, 2017-03783] Funding Source: Swedish Research Council
- Vinnova [2019-01085] Funding Source: Vinnova
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The target protection proteins provide resistance to Gram-positive bacteria by directly binding to the antibiotic target. The research reveals the mechanism by which ABC proteins F-subtype bind to the ribosome to mediate antibiotic release. Understanding these resistance mechanisms is crucial for the future development of antibiotics.
Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaA(LC) and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms. Mitochondrial ribosomes (mitoribosomes) are characterized by a distinct architecture and thus biogenesis pathway. Here, cryo-EM structures of mitoribosome large subunit assembly intermediates elucidate final steps of 16S rRNA folding, methylation and peptidyl transferase centre (PTC) completion, as well as functions of several mitoribosome assembly factors.
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