期刊
NUCLEIC ACIDS RESEARCH
卷 46, 期 7, 页码 3753-3763出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky050
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资金
- European Regional Development Fund through the Centre of Excellence for Molecular Cell Engineering
- Molecular Infection Medicine Sweden (MIMS)
- Swedish Research council [2013-4680, 2015-04746]
- Ragnar Soderbergs Stiftelse
- Carl Tryggers Stiftelse for Vetenskaplig Forskning [CTS 14:34, CTS 15:35]
- Kempestiftelserna [JCK-1627]
- Jeanssons Stiftelser
- Umea Universitet Insamlingsstiftelsen for medicinsk forskning
- Umea Centre for Microbial Research (UCMR) Gender Policy Programme
- Swedish Research Council [2015-04746] Funding Source: Swedish Research Council
Several ATPases in the ATP-binding cassette F (ABCF) family confer resistance to macrolides, lincosamides and streptogramins (MLS) antibiotics. MLS are structurally distinct classes, but inhibit a common target: the peptidyl transferase (PTC) active site of the ribosome. Antibiotic resistance (ARE) ABCFs have recently been shown to operate through direct ribosomal protection, but the mechanistic details of this resistance mechanism are lacking. Using a reconstituted translational system, we dissect the molecular mechanism of Staphylococcus haemolyticus VgaA(LC) and Enterococcus faecalis LsaA on the ribosome. We demonstrate that VgaA(LC) is an NTPase that operates as a molecular machine strictly requiring NTP hydrolysis (not just NTP binding) for antibiotic protection. Moreover, when bound to the ribosome in the NTP-bound form, hydrolytically inactive EQ(2) ABCF ARE mutants inhibit peptidyl transferase activity, suggesting a direct interaction between the ABCF ARE and the PTC. The likely structural candidate responsible for antibiotic displacement by wild type ABCF AREs, and PTC inhibition by the EQ(2) mutant, is the extended inter-ABC domain linker region. Deletion of the linker region renders wild type VgaA(LC) inactive in antibiotic protection and the EQ(2) mutant inactive in PTC inhibition.
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