Structural basis of lipoprotein signal peptidase II action and inhibition by the antibiotic globomycin

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Science  19 Feb 2016:
Vol. 351, Issue 6275, pp. 876-880
DOI: 10.1126/science.aad3747

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Insight into a bacterial membrane protease

Lipoproteins have key functions in many bacteria. They are synthesized in a precursor form that requires processing by enzymes that are essential in many pathogenic bacteria but have no equivalent in humans, making them potential drug targets. LspA is a key membrane protein involved in lipoprotein maturation in the bacterium Pseudomonas aeruginosa. Vogeley et al. determined the crystal structure of LspA bound to the antibiotic globomycin. Their structure and mutagenesis studies reveal how LspA processes substrate lipoproteins and indicate that globomycin inhibits the enzyme by binding to the active site. These findings should be useful in the development of new antibiotics.

Science, this issue p. 876


With functions that range from cell envelope structure to signal transduction and transport, lipoproteins constitute 2 to 3% of bacterial genomes and play critical roles in bacterial physiology, pathogenicity, and antibiotic resistance. Lipoproteins are synthesized with a signal peptide securing them to the cytoplasmic membrane with the lipoprotein domain in the periplasm or outside the cell. Posttranslational processing requires a signal peptidase II (LspA) that removes the signal peptide. Here, we report the crystal structure of LspA from Pseudomonas aeruginosa complexed with the antimicrobial globomycin at 2.8 angstrom resolution. Mutagenesis studies identify LspA as an aspartyl peptidase. In an example of molecular mimicry, globomycin appears to inhibit by acting as a noncleavable peptide that sterically blocks the active site. This structure should inform rational antibiotic drug discovery.

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