9c3f

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Bacteria invest significant resources into the continuous creation and tailoring of their essential protective peptidoglycan (PG) cell wall. Several soluble PG biosynthesis products in the periplasm are transported to the cytosol for recycling, leading to enhanced bacterial fitness. GlcNAc-1,6-anhydroMurNAc and peptide variants are transported by the essential major facilitator superfamily importer AmpG in Gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Accumulation of GlcNAc-1,6-anhydroMurNAc-pentapeptides also results from beta-lactam antibiotic induced cell wall damage. In some species, these products upregulate the beta-lactamase AmpC, which hydrolyzes beta-lactams to allow for bacterial survival and drug-resistant infections. Here, we have used cryo-electron microscopy and chemical synthesis of substrates in an integrated structural, biochemical, and cellular analysis of AmpG. We show how AmpG accommodates the large GlcNAc-1,6-anhydroMurNAc peptides, including a unique hydrophobic vestibule to the substrate binding cavity, and characterize residues involved in binding that inform the mechanism of proton-mediated transport.
Bacteria invest significant resources into the continuous creation and tailoring of their essential protective peptidoglycan (PG) cell wall. Several soluble PG biosynthesis products in the periplasm are transported to the cytosol for recycling, leading to enhanced bacterial fitness. GlcNAc-1,6-anhydroMurNAc and peptide variants are transported by the essential major facilitator superfamily importer AmpG in Gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Accumulation of GlcNAc-1,6-anhydroMurNAc-pentapeptides also results from beta-lactam antibiotic induced cell wall damage. In some species, these products upregulate the beta-lactamase AmpC, which hydrolyzes beta-lactams to allow for bacterial survival and drug-resistant infections. Here, we have used cryo-electron microscopy and chemical synthesis of substrates in an integrated structural, biochemical, and cellular analysis of AmpG. We show how AmpG accommodates the large GlcNAc-1,6-anhydroMurNAc peptides, including a unique hydrophobic vestibule to the substrate binding cavity, and characterize residues involved in binding that inform the mechanism of proton-mediated transport.
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Cryo-EM characterization of the anydromuropeptide permease AmpG central to bacterial fitness and beta-lactam antibiotic resistance.,Sverak HE, Yaeger LN, Worrall LJ, Vacariu CM, Glenwright AJ, Vuckovic M, Al Azawi ZD, Lamers RP, Marko VA, Skorupski C, Soni AS, Tanner ME, Burrows LL, Strynadka NC Nat Commun. 2024 Nov 16;15(1):9936. doi: 10.1038/s41467-024-54219-9. PMID:39548104<ref>PMID:39548104</ref>
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, PMID:39548104<ref>PMID:39548104</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Current revision

Cryo-EM structure of E. coli AmpG

PDB ID 9c3f

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