Structural basis for antibiotic resistance mediated by the
            <i>Bacillus subtilis</i>
            ABCF ATPase VmlR

Crowe‐McAuliffe, Caillan; Graf, Michael; Huter, Paul; Takada, Hiraku; Abdelshahid, Maha; Nováček, Jiří; Murina, Victoriia; Atkinson, Gemma C.; Hauryliuk, Vasili; Wilson, Daniel N.

doi:10.1073/pnas.1808535115

Cited by 87 publications

(268 citation statements)

References 43 publications

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“…B. subtilis and E. coli strains (Crowe-McAuliffe et al, 2018;Guerout-Fleury et al, 1996;Guerout-Fleury et al, 1995;Horinouchi and Weisblum, 1982;Murina et al, 2019;Takada et al, 2014) used in this study are listed in Table S3. All B. subtilis strains used were derivatives of the wild-type 168 strain.…”

Section: Bacterial Strainsmentioning

confidence: 99%

Structural basis for bacterial ribosome quality control

Crowe‐McAuliffe

Takada

Murina

et al. 2020

Preprint

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SummaryIn all branches of life, stalled translation intermediates are recognized and processed by ribosome-associated quality-control (RQC) pathways. RQC begins with splitting of stalled ribosomes, leaving an unfinished polypeptide still attached to the large subunit. Ancient and conserved NEMF family RQC proteins target these incomplete proteins for degradation by the addition of C-terminal ‘tails.’ How such tailing can occur without the regular suite of translational components is, however, unclear. Using ex vivo single-particle cryo-EM, we show that C-terminal tailing in Bacillus subtilis is mediated by NEMF protein RqcH in concert with YabO, a protein homologous to, yet distinct from, Hsp15. Our structures reveal how these factors mediate tRNA movement across the ribosomal 50S subunit to synthesize polypeptides in the absence of mRNA or the small subunit.

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Section: Bacterial Strainsmentioning

confidence: 99%

Structural basis for bacterial ribosome quality control

Crowe‐McAuliffe

Takada

Murina

et al. 2020

Preprint

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“…Here again, one of the ATP molecules could be used to reset of the system after the protein has identified the ribosomes inhibited by the antibiotic. To be sure, experimental evidence has established that antibiotic resistance ABC-F proteins reset the peptidyl transferase centre of the ribosome to counter translational arrest (Crowe-McAuliffe et al, 2018;Murina et al, 2018).…”

Section: Accurate Template Recognition During Translation and Antibiomentioning

confidence: 99%

Omnipresent Maxwell's demons orchestrate information management in living cells

Boël

Danot

Lorenzo

et al. 2019

Microbial Biotechnology

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Summary The development of synthetic biology calls for accurate understanding of the critical functions that allow construction and operation of a living cell. Besides coding for ubiquitous structures, minimal genomes encode a wealth of functions that dissipate energy in an unanticipated way. Analysis of these functions shows that they are meant to manage information under conditions when discrimination of substrates in a noisy background is preferred over a simple recognition process. We show here that many of these functions, including transporters and the ribosome construction machinery, behave as would behave a material implementation of the information‐managing agent theorized by Maxwell almost 150 years ago and commonly known as Maxwell's demon (MxD). A core gene set encoding these functions belongs to the minimal genome required to allow the construction of an autonomous cell. These MxDs allow the cell to perform computations in an energy‐efficient way that is vastly better than our contemporary computers.

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“…Based on the complex model, ABC1 and ABC2 of SrpA established massive interactions with ribosomal protein and the elbow of the P-tRNA, while the interdomain linker, especially the extended loop region, projected deep into the ribosome PTC, interacted with the CCA arm of P-tRNA, and was located in proximity to 23S rRNA helices H89 and H73. The architecture and conformation of the SrpAribosome interactions were very similar to those of MsrE/VmlR, suggesting that the binding site of antibiotic resistance ABC-F proteins is highly conserved [23,24]. Valnemulin-ribosome docked compounds revealed that the tricyclic mutilin core on the base of C2452, U2505, U2506, A2062, G2061, and its C14 extension was stabilized by U2585 [2,13,14].…”

Section: Discussionmentioning

confidence: 89%

“…Several studies have demonstrated that antibiotic resistance ABC-F proteins bind to the ribosome and allosterically dissociate the drug from its binding site [23,24]. In the present work, molecular docking was used to analyze SrpA-ribosome interactions.…”

Section: Homology Modeling and Molecular Docking Of Srpamentioning

confidence: 99%

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Characterization of a novel gene,srpA, conferring resistance to streptogramin A, pleuromutilins, and lincosamides inStreptococcus suis

Zhang¹,

Liu²,

Zhang³

et al. 2020

Preprint

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Antimicrobial resistance is undoubtedly one of the greatest global health threats. The emergence of multidrug resistant (MDR) gram positive pathogens, like methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and β-lactamase resistant Streptococcus pneumonia, has severely limited our antibiotic arsenal. Numerous ribosome-targeting antibiotics, especially pleuromutilins, oxazolidinones, and streptogramins, are viewed as promising alternatives against aggressive MDR pathogens. In this study, we identified a new ABC F family determinant, srpA, in Streptococcus suis by a comparative analysis of whole genome sequences of tiamulin resistant and sensitive bacteria. Functional cloning confirmed that the deduced gene can mediate cross-resistance to pleuromutilins, lincosamides, and streptogramin A in S. suis and S. aureus. A sequence alignment revealed that srpA shares the highest amino acid identity with Vga(E) (36%) and shows canonical characteristics of ABC F family members. In SrpA ribosome docked compounds, the extended loop region of SrpA approaches the valnemulin binding pocket in the ribosome peptidyl transferase center and competes with bound valnemulin. A detailed mutational analysis of the loop residues confirmed that this domain is crucial for SrpA activity, as substitutions or truncations of this region affect the efficiency and specificity of antibiotic resistance. A ribosome binding assay supported the protective effects of SrpA on the ribosome by preventing antibiotic binding as well as displacing bound drugs. These findings clarify the mechanisms underlying resistance to ribosomal antibiotics.

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Structural basis for antibiotic resistance mediated by the Bacillus subtilis ABCF ATPase VmlR

Cited by 87 publications

References 43 publications

Structural basis for bacterial ribosome quality control

Structural basis for bacterial ribosome quality control

Omnipresent Maxwell's demons orchestrate information management in living cells

Characterization of a novel gene,srpA, conferring resistance to streptogramin A, pleuromutilins, and lincosamides inStreptococcus suis

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