Structure of the essential inner membrane lipopolysaccharide–PbgA complex

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

doi:10.1038/s41586-020-2597-x

Title: Structure of the essential inner membrane lipopolysaccharide–PbgA complex

Journal Article · Wed Aug 12 00:00:00 EDT 2020 · Nature (London)

DOI:https://doi.org/10.1038/s41586-020-2597-x· OSTI ID:1656545

^[1];

^[2]; Li, Qingling ^[3]; Verschueren, Erik ^[3]; Liu, Peter ^[3]; Sangaraju, Dewakar ^[4]; Park, Summer ^[5]; Noland, Cameron L. ^[1];

^[2]; Nickerson, Nicholas N. ^[2]; Martin, Lynn ^[6]; Dela Vega, Trisha ^[6]; Miu, Anh ^[7];

^[8]; Ruiz-Gonzalez, Maria ^[9]; Swem, Danielle ^[2];

^[3]; DePonte, Daniel P. ^[10];

^[10];

^[11] more »

Genentech, San Francisco, CA (United States). Structural Biology
Genentech, San Francisco, CA (United States). Infectious Diseases
Genentech, San Francisco, CA (United States). Microchemistry, Proteomics & Lipidomics
Genentech, San Francisco, CA (United States). Drug Metabolism & Pharmacokinetics
Genentech, San Francisco, CA (United States). Translational Immunology
Genentech, San Francisco, CA (United States). BioMolecular Resources
Genentech, San Francisco, CA (United States). Biochemical & Cellular Pharmacology
Genentech, San Francisco, CA (United States). Bioinformatics & Computational Biology
Genentech, San Francisco, CA (United States). Discovery Chemistry Dept.
SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS)
SLAC National Accelerator Lab., Menlo Park, CA (United States). Bioscience Division; Stanford Univ., CA (United States). Dept. of Structural Biology
Genentech, San Francisco, CA (United States). Structural Biology and Infectious Diseases

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.

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Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515; P41GM103393

OSTI ID:: 1656545

Journal Information:: Nature (London), Vol. 584, Issue 7821; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 38 works

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