Structure of the essential inner membrane lipopolysaccharide–PbgA complex

Thomas Clairfeuille, Kerry R. Buchholz, Qingling Li, Erik Verschueren, Peter Liu, Dewakar Sangaraju, Summer Park, Cameron L. Noland, Kelly M. Storek, Nicholas N. Nickerson, Lynn Martin, Trisha Vega, Anh Miu, Janina Reeder, Maria Ruiz-Gonzalez, Danielle Swem, Guanghui Han, Daniel P. DePonte, Mark S. Hunter, Cornelius Gati, Sheerin Shahidi-Latham, Min Xu, Nicholas Skelton, Benjamin D. Sellers, Elizabeth Skippington, Wendy Sandoval, Emily J. Hanan (), Jian Payandeh () and Steven T. Rutherford ()
Additional contact information
Thomas Clairfeuille: Genentech Inc.
Kerry R. Buchholz: Genentech Inc.
Qingling Li: Genentech Inc.
Erik Verschueren: Genentech Inc.
Peter Liu: Genentech Inc.
Dewakar Sangaraju: Genentech Inc.
Summer Park: Genentech Inc.
Cameron L. Noland: Genentech Inc.
Kelly M. Storek: Genentech Inc.
Nicholas N. Nickerson: Genentech Inc.
Lynn Martin: Genentech Inc.
Trisha Vega: Genentech Inc.
Anh Miu: Genentech Inc.
Janina Reeder: Genentech Inc.
Maria Ruiz-Gonzalez: Genentech Inc.
Danielle Swem: Genentech Inc.
Guanghui Han: Genentech Inc.
Daniel P. DePonte: SLAC National Accelerator Laboratory
Mark S. Hunter: SLAC National Accelerator Laboratory
Cornelius Gati: SLAC National Accelerator Laboratory
Sheerin Shahidi-Latham: Genentech Inc.
Min Xu: Genentech Inc.
Nicholas Skelton: Genentech Inc.
Benjamin D. Sellers: Genentech Inc.
Elizabeth Skippington: Genentech Inc.
Wendy Sandoval: Genentech Inc.
Emily J. Hanan: Genentech Inc.
Jian Payandeh: Genentech Inc.
Steven T. Rutherford: Genentech Inc.

Nature, 2020, vol. 584, issue 7821, 479-483

Abstract: Abstract Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function1,2. LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics3,4. Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains5, 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 transporter6–9, 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 enzyme10–12. 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.

Date: 2020
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DOI: 10.1038/s41586-020-2597-x

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