4v36

The structure of L-PGS from Bacillus licheniformis

spinqualitylabelsall models 4v36, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4v36 is a 2 chain structure with sequence from Bacillus licheniformis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: LYN, TRS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q65MA9_BACLD Catalyzes the transfer of a lysyl group from L-lysyl-tRNA(Lys) to membrane-bound phosphatidylglycerol (PG), which produces lysylphosphatidylglycerol (LPG), a major component of the bacterial membrane with a positive net charge. LPG synthesis contributes to bacterial virulence as it is involved in the resistance mechanism against cationic antimicrobial peptides (CAMP) produces by the host's immune system (defensins, cathelicidins) and by the competing microorganisms.[RuleBase:RU363042] Publication Abstract from PubMed 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-tRNAAla-dependent alanyl-phosphatidylglycerol synthase (A-PGS) or by Lys-tRNALys-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. Structures of two bacterial resistance factors mediating tRNA-dependent aminoacylation of phosphatidylglycerol with lysine or alanine.,Hebecker S, Krausze J, Hasenkampf T, Schneider J, Groenewold M, Reichelt J, Jahn D, Heinz DW, Moser J Proc Natl Acad Sci U S A. 2015 Aug 10. pii: 201511167. PMID:26261323 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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