6XLP

Structure of the essential inner membrane lipopolysaccharide-PbgA complex

Summary for 6XLP

• Entry DOI: 10.2210/pdb6xlp/pdb
• Descriptor: LPS binding protein, 2-deoxy-3-O-[(1R,3R)-1,3-dihydroxytetradecyl]-2-{[(3R)-3-hydroxytetradecanoyl]amino}-1-O-phosphono-alpha-D-glucopyranose-(6-1)-[3-deoxy-alpha-D-manno-oct-2-ulopyranosonic acid-(2-6)]1,5-anhydro-2-deoxy-2-{[(1S,3R)-1-hydroxy-3-(pentanoyloxy)undecyl]amino}-4-O-phosphono-D-glucitol, SULFATE ION, ... (7 entities in total)
• Functional Keywords: lipopolysaccharide, lps; membrane protein, lipid binding protein
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 74889.06

Authors

Payandeh, J.,Clairefeuille, T. (deposition date: 2020-06-29, release date: 2020-08-26, Last modification date: 2023-10-18)

Primary citation

Clairfeuille, T.,Buchholz, K.R.,Li, Q.,Verschueren, E.,Liu, P.,Sangaraju, D.,Park, S.,Noland, C.L.,Storek, K.M.,Nickerson, N.N.,Martin, L.,Dela Vega, T.,Miu, A.,Reeder, J.,Ruiz-Gonzalez, M.,Swem, D.,Han, G.,DePonte, D.P.,Hunter, M.S.,Gati, C.,Shahidi-Latham, S.,Xu, M.,Skelton, N.,Sellers, B.D.,Skippington, E.,Sandoval, W.,Hanan, E.J.,Payandeh, J.,Rutherford, S.T.
Structure of the essential inner membrane lipopolysaccharide-PbgA complex.
Nature, 584:479-483, 2020

PubMed Abstract: Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function. LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics. Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains, our understanding of the bacterial factors that regulate LPS biogenesis is incomplete. Here we characterize the inner membrane protein PbgA and report that its depletion attenuates the virulence of Escherichia coli by reducing levels of LPS and outer membrane integrity. In contrast to previous claims that PbgA functions as a cardiolipin transporter, our structural analyses and physiological studies identify a lipid A-binding motif along the periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides selectively bind to LPS in vitro and inhibit the growth of diverse Gram-negative bacteria, including polymyxin-resistant strains. Proteomic, genetic and pharmacological experiments uncover a model in which direct periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme. In summary, we find that PbgA has an unexpected but essential role in the regulation of LPS biogenesis, presents a new structural basis for the selective recognition of lipids, and provides opportunities for future antibiotic discovery.

PubMed: 32788728
DOI: 10.1038/s41586-020-2597-x

Experimental method

X-RAY DIFFRACTION (2 Å)