3s04

Crystal structure of Escherichia coli type I signal peptidase in complex with an Arylomycin Lipoglycopeptide Antibiotic

spinqualitylabelsall models 3s04, resolution 2.44Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3s04 is a 4 chain structure with sequence from Ecoli and Streptomyces sp.. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 02U, RAM NonStd Res: 02V, DAL, DSE Related: 1b12, 1t7d, 3iiq, 1kn9 Gene: b2568, JW2552, lepB (ECOLI) Activity: Signal peptidase I, with EC number 3.4.21.89 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Glycosylation of natural products, including antibiotics, often plays an important role in determining their physical properties and their biological activity, and thus their potential as drug candidates. The arylomycin class of antibiotics inhibits bacterial type I signal peptidase and is comprised of three related series of natural products with a lipopeptide tail attached to a core macrocycle. Previously, we reported the total synthesis of several A series derivatives, which have unmodified core macrocycles, as well as B series derivatives, which have a nitrated macrocycle. We now report the synthesis and biological evaluation of lipoglycopeptide arylomycin variants whose macrocycles are glycosylated with a deoxy-alpha-mannose substituent, and also in some cases hydroxylated. The synthesis of the derivatives bearing each possible deoxy-alpha-mannose enantiomer allowed us to assign the absolute stereochemistry of the sugar in the natural product and also to show that while glycosylation does not alter antibacterial activity, it does appear to improve solubility. Crystallographic structural studies of a lipoglycopeptide arylomycin bound to its signal peptidase target reveal the molecular interactions that underlie inhibition and also that the mannose is directed away from the binding site into solvent which suggests that other modifications may be made at the same position to further increase solubility and thus reduce protein binding and possibly optimize the pharmacokinetics of the scaffold. Synthesis and Characterization of the Arylomycin Lipoglycopeptide Antibiotics and the Crystallographic Analysis of Their Complex with Signal Peptidase.,Liu J, Luo C, Smith PA, Chin JK, Page MG, Paetzel M, Romesberg FE J Am Chem Soc. 2011 Oct 14. PMID:21999324 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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