ArticleProceedings of the National Academy of Sciences of the United States of America2015
Structures of two bacterial resistance factors mediating tRNA-dependent aminoacylation of phosphatidylglycerol with lysine or alanine.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 46 citations in OpenAlex.
- Cryo-EM structures of multiple-peptide resistance factor (MprF) from Pseudomonas aeruginosa.The FEBS journal · 2026Article
- Structure of ergosteryl-aspartate synthase reveals how an entrapped tRNA is used like a prosthetic swinging arm in the synthesis of aminoacylated sterols.Nature communications · 2026Article
- Structural basis of substrate recognition and membrane association by the bacterial lysyl-phosphatidylglycerol hydrolase AcvB.Communications biology · 2026Article
- Biosynthesis of glucosaminyl phosphatidylglycerol inJournal of bacteriology · 2025Article
- MprF fromScience advances · 2025Article
- Article
- The MprF homolog LysX synthesizes lysyl-diacylglycerol contributing to antibiotic resistance and virulence.Microbiology spectrum · 2023Article
- The structural basis of tRNA recognition by arginyl-tRNA-protein transferase.Nature communications · 2023Article
- Article
- Amino-acyl tXNA as inhibitors or amino acid donors in peptide synthesis.Nucleic acids research · 2022Article
- Harnessing the Role of Bacterial Plasma Membrane Modifications for the Development of Sustainable Membranotropic Phytotherapeutics.Membranes · 2022Review
- Crystal structure of the Ate1 arginyl-tRNA-protein transferase and arginylation of N-degron substrates.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Identification of a novel cationic glycolipid in Streptococcus agalactiae that contributes to brain entry and meningitis.PLoS biology · 2022Article
- Structure-based modeling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant present at the cytoplasmic membrane.Structure (London, England : 1993) · 2021Article
- Phospholipid translocation captured in a bifunctional membrane protein MprF.Nature communications · 2021Article
- Expansion of the Major Facilitator Superfamily (MFS) to include novel transporters as well as transmembrane-acting enzymes.Biochimica et biophysica acta. Biomembranes · 2020Article
- RNA-dependent sterol aspartylation in fungi.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Small-Molecule Acetylation by GCN5-RelatedMicrobiology and molecular biology reviews : MMBR · 2020Review
- Mechanism of regulation and neutralization of the AtaR-AtaT toxin-antitoxin system.Nature chemical biology · 2019Article
- Investigation of Amide Bond Formation during Dehydrophos Biosynthesis.ACS chemical biology · 2018Article
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9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The cytoplasmic membrane is probably the most important physical barrier between microbes and the surrounding habitat. Aminoacylation of the polar head group of the phospholipid phosphatidylglycerol (PG) catalyzed by Ala-tRNA(Ala)-dependent alanyl-phosphatidylglycerol synthase (A-PGS) or by Lys-tRNA(Lys)-dependent lysyl-phosphatidylglycerol synthase (L-PGS) enables bacteria to cope with cationic peptides that are harmful to the integrity of the cell membrane. Accordingly, these synthases also have been designated as multiple peptide resistance factors (MprF). They consist of a separable C-terminal catalytic domain and an N-terminal transmembrane flippase domain. Here we present the X-ray crystallographic structure of the catalytic domain of A-PGS from the opportunistic human pathogen Pseudomonas aeruginosa. In parallel, the structure of the related lysyl-phosphatidylglycerol-specific L-PGS domain from Bacillus licheniformis in complex with the substrate analog L-lysine amide is presented. Both proteins reveal a continuous tunnel that allows the hydrophobic lipid substrate PG and the polar aminoacyl-tRNA substrate to access the catalytic site from opposite directions. Substrate recognition of A-PGS versus L-PGS was investigated using misacylated tRNA variants. The structural work presented here in combination with biochemical experiments using artificial tRNA or artificial lipid substrates reveals the tRNA acceptor stem, the aminoacyl moiety, and the polar head group of PG as the main determinants for substrate recognition. A mutagenesis approach yielded the complementary amino acid determinants of tRNA interaction. These results have broad implications for the design of L-PGS and A-PGS inhibitors that could render microbial pathogens more susceptible to antimicrobial compounds.
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