3S04

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

Summary for 3S04

• Entry DOI: 10.2210/pdb3s04/pdb
• Related: 1B12 1KN9 1T7D 3IIQ
• Related PRD ID: PRD_000813
• Descriptor: Signal peptidase I, Glyco-Arylomycin, 14-methylhexadec-9-enoic acid, ... (5 entities in total)
• Functional Keywords: mostly-beta fold, membrane bound, serine protease, secreted preproteins, cytoplasmic membrane, hydrolase-antibiotic complex, signal peptidase, leader peptidase, signal peptide, leader peptide, serine-lysine dyad, hydrolase/antibiotic
• Biological source: Escherichia coli; More
• Cellular location: Cell inner membrane; Multi-pass membrane protein: P00803
• Total number of polymer chains: 4
• Total formula weight: 58346.16

Authors

Paetzel, M.,Luo, C. (deposition date: 2011-05-13, release date: 2011-10-05, Last modification date: 2023-12-06)

Primary citation

Liu, J.,Luo, C.,Smith, P.A.,Chin, J.K.,Page, M.G.,Paetzel, M.,Romesberg, F.E.
Synthesis and characterization of the arylomycin lipoglycopeptide antibiotics and the crystallographic analysis of their complex with signal peptidase.
J.Am.Chem.Soc., 133:17869-17877, 2011

PubMed Abstract: 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-α-mannose substituent, and also in some cases hydroxylated. The synthesis of the derivatives bearing each possible deoxy-α-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.

PubMed: 21999324
DOI: 10.1021/ja207318n

Experimental method

X-RAY DIFFRACTION (2.44 Å)