6B8B

E. coli LptB in complex with ADP and a novobiocin derivative

Summary for 6B8B

• Entry DOI: 10.2210/pdb6b8b/pdb
• Related: 6B89
• Descriptor: Lipopolysaccharide export system ATP-binding protein LptB, MAGNESIUM ION, (3s,5s,7s)-N-{7-[(3-O-carbamoyl-6-deoxy-5-methyl-4-O-methyl-beta-D-gulopyranosyl)oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-ben zopyran-3-yl}tricyclo[3.3.1.1~3,7~]decane-1-carboxamide, ... (5 entities in total)
• Functional Keywords: lptb, abc transporter, lps transport, lipid transport, lipid transport-activator complex, lipid transport/activator
• Biological source: Escherichia coli (strain K12)
• Total number of polymer chains: 1
• Total formula weight: 28978.90

Authors

Mandler, M.D.,Owens, T.W.,Lazarus, M.B.,May, J.M.,Kahne, D.K. (deposition date: 2017-10-06, release date: 2017-12-06, Last modification date: 2023-10-04)

Primary citation

May, J.M.,Owens, T.W.,Mandler, M.D.,Simpson, B.W.,Lazarus, M.B.,Sherman, D.J.,Davis, R.M.,Okuda, S.,Massefski, W.,Ruiz, N.,Kahne, D.
The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport.
J. Am. Chem. Soc., 139:17221-17224, 2017

PubMed Abstract: Novobiocin is an orally active antibiotic that inhibits DNA gyrase by binding the ATP-binding site in the ATPase subunit. Although effective against Gram-positive pathogens, novobiocin has limited activity against Gram-negative organisms due to the presence of the lipopolysaccharide-containing outer membrane, which acts as a permeability barrier. Using a novobiocin-sensitive Escherichia coli strain with a leaky outer membrane, we identified a mutant with increased resistance to novobiocin. Unexpectedly, the mutation that increases novobiocin resistance was not found to alter gyrase, but the ATPase that powers lipopolysaccharide (LPS) transport. Co-crystal structures, biochemical, and genetic evidence show novobiocin directly binds this ATPase. Novobiocin does not bind the ATP binding site but rather the interface between the ATPase subunits and the transmembrane subunits of the LPS transporter. This interaction increases the activity of the LPS transporter, which in turn alters the permeability of the outer membrane. We propose that novobiocin will be a useful tool for understanding how ATP hydrolysis is coupled to LPS transport.

PubMed: 29135241
DOI: 10.1021/jacs.7b07736

Experimental method

X-RAY DIFFRACTION (1.95 Å)