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Structure of UDP-N-acetylglucosamine acyltransferase with a bound antibacterial pentadecapeptide.

Williams AH, Immormino RM, Gewirth DT, Raetz CR
Proc Natl Acad Sci U S A 103 10877-82 (2006)
Cited: 42 times
EuropePMC logo PMID: 16835299

Abstract

UDP-GlcNAc acyltransferase (LpxA) catalyzes the first step of lipid A biosynthesis, the transfer of the R-3-hydroxyacyl chain from R-3-hydroxyacyl acyl carrier protein (ACP) to the glucosamine 3-OH group of UDP-GlcNAc. LpxA is essential for the growth of Escherichia coli and related Gram-negative bacteria. The crystal structure of the E. coli LpxA homotrimer, determined previously at 2.6 A in the absence of substrates or inhibitors, revealed that LpxA contains an unusual, left-handed parallel beta-helix fold. We now present the crystal structure at 1.8 A resolution of E. coli LpxA in a complex with a pentadecapeptide, peptide 920. Three peptides, each of which adopts a beta-hairpin conformation, are bound per LpxA trimer. The peptides are located at the interfaces of adjacent subunits in the vicinity of the three active sites. Each peptide interacts with residues from both adjacent subunits. Peptide 920 is a potent inhibitor of E. coli LpxA (Ki = 50 nM). It is competitive with respect to acyl-ACP but not UDP-GlcNAc. The compact beta-turn structure of peptide 920 bound to LpxA may open previously uncharacterized approaches to the rational design of LpxA inhibitors with antibiotic activity.

Reviews - 2aq9 mentioned but not cited (1)

  1. Structure, inhibition, and regulation of essential lipid A enzymes. Zhou P, Zhao J. Biochim Biophys Acta Mol Cell Biol Lipids 1862 1424-1438 (2017)

Articles - 2aq9 mentioned but not cited (7)

  1. Benchmarking of different molecular docking methods for protein-peptide docking. Agrawal P, Singh H, Srivastava HK, Singh S, Kishore G, Raghava GPS. BMC Bioinformatics 19 426 (2019)
  2. Structure of UDP-N-acetylglucosamine acyltransferase with a bound antibacterial pentadecapeptide. Williams AH, Immormino RM, Gewirth DT, Raetz CR. Proc Natl Acad Sci U S A 103 10877-10882 (2006)
  3. Structural basis for the recognition of peptide RJPXD33 by acyltransferases in lipid A biosynthesis. Jenkins RJ, Heslip KA, Meagher JL, Stuckey JA, Dotson GD. J Biol Chem 289 15527-15535 (2014)
  4. Structure determination of LpxA from the lipopolysaccharide-synthesis pathway of Acinetobacter baumannii. Badger J, Chie-Leon B, Logan C, Sridhar V, Sankaran B, Zwart PH, Nienaber V. Acta Crystallogr Sect F Struct Biol Cryst Commun 68 1477-1481 (2012)
  5. Structure guided design of an antibacterial peptide that targets UDP-N-acetylglucosamine acyltransferase. Dangkulwanich M, Raetz CRH, Williams AH. Sci Rep 9 3947 (2019)
  6. Crystal structure and activity of Francisella novicida UDP-N-acetylglucosamine acyltransferase. Joo SH, Chung HS. Biochem Biophys Res Commun 478 1223-1229 (2016)
  7. Non-steric-zipper models for pathogenic α-synuclein conformers. Schuman B, Won A, Brand-Arzamendi K, Koprich JB, Wen XY, Howson PA, Brotchie JM, Yip CM. APL Bioeng 2 026105 (2018)


Reviews citing this publication (8)

  1. Lipid A modification systems in gram-negative bacteria. Raetz CR, Reynolds CM, Trent MS, Bishop RE. Annu Rev Biochem 76 295-329 (2007)
  2. Biosynthesis and export of bacterial lipopolysaccharides. Whitfield C, Trent MS. Annu Rev Biochem 83 99-128 (2014)
  3. Lipopolysaccharide: Biosynthetic pathway and structure modification. Wang X, Quinn PJ. Prog Lipid Res 49 97-107 (2010)
  4. Antibacterial activities of anthraquinones: structure-activity relationships and action mechanisms. Qun T, Zhou T, Hao J, Wang C, Zhang K, Xu J, Wang X, Zhou W. RSC Med Chem 14 1446-1471 (2023)
  5. Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action. Ostroumova OS, Efimova SS. Antibiotics (Basel) 12 1716 (2023)
  6. Phage Display-Derived Peptides and Antibodies for Bacterial Infectious Diseases Therapy and Diagnosis. Zhao H, Nie D, Hu Y, Chen Z, Hou Z, Li M, Xue X. Molecules 28 2621 (2023)
  7. Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance. Romano KP, Hung DT. Biochim Biophys Acta Mol Cell Res 1870 119407 (2023)
  8. Using Structure-guided Fragment-Based Drug Discovery to Target Pseudomonas aeruginosa Infections in Cystic Fibrosis. Arif SM, Floto RA, Blundell TL. Front Mol Biosci 9 857000 (2022)

Articles citing this publication (26)

  1. Structural basis for the acyl chain selectivity and mechanism of UDP-N-acetylglucosamine acyltransferase. Williams AH, Raetz CR. Proc Natl Acad Sci U S A 104 13543-13550 (2007)
  2. Structure and reactivity of LpxD, the N-acyltransferase of lipid A biosynthesis. Buetow L, Smith TK, Dawson A, Fyffe S, Hunter WN. Proc Natl Acad Sci U S A 104 4321-4326 (2007)
  3. Chasing acyl carrier protein through a catalytic cycle of lipid A production. Masoudi A, Raetz CR, Zhou P, Pemble CW. Nature 505 422-426 (2014)
  4. Steady-state kinetics and mechanism of LpxD, the N-acyltransferase of lipid A biosynthesis. Bartling CM, Raetz CR. Biochemistry 47 5290-5302 (2008)
  5. High-throughput screening identifies novel inhibitors of the acetyltransferase activity of Escherichia coli GlmU. Pereira MP, Blanchard JE, Murphy C, Roderick SL, Brown ED. Antimicrob Agents Chemother 53 2306-2311 (2009)
  6. Acyl chain specificity of the acyltransferases LpxA and LpxD and substrate availability contribute to lipid A fatty acid heterogeneity in Porphyromonas gingivalis. Bainbridge BW, Karimi-Naser L, Reife R, Blethen F, Ernst RK, Darveau RP. J Bacteriol 190 4549-4558 (2008)
  7. Dual targeting antibacterial peptide inhibitor of early lipid A biosynthesis. Jenkins RJ, Dotson GD. ACS Chem Biol 7 1170-1177 (2012)
  8. Structural basis for the sugar nucleotide and acyl-chain selectivity of Leptospira interrogans LpxA. Robins LI, Williams AH, Raetz CR. Biochemistry 48 6191-6201 (2009)
  9. Structural and kinetic characterizations of the polysialic acid O-acetyltransferase OatWY from Neisseria meningitidis. Lee HJ, Rakić B, Gilbert M, Wakarchuk WW, Withers SG, Strynadka NC. J Biol Chem 284 24501-24511 (2009)
  10. A comprehensive proteome map of the Haemophilus parasuis serovar 5. Zhou M, Zhang A, Guo Y, Liao Y, Chen H, Jin M. Proteomics 9 2722-2739 (2009)
  11. Nucleotide substrate recognition by UDP-N-acetylglucosamine acyltransferase (LpxA) in the first step of lipid A biosynthesis. Ulaganathan V, Buetow L, Hunter WN. J Mol Biol 369 305-312 (2007)
  12. Crystal structure of LpxK, the 4'-kinase of lipid A biosynthesis and atypical P-loop kinase functioning at the membrane interface. Emptage RP, Daughtry KD, Pemble CW, Raetz CR. Proc Natl Acad Sci U S A 109 12956-12961 (2012)
  13. Lipophilic sugar nucleotide synthesis by structure-based design of nucleotidylyltransferase substrates. Huestis MP, Aish GA, Hui JP, Soo EC, Jakeman DL. Org Biomol Chem 6 477-484 (2008)
  14. Periodontitis in elderly patients with type 2 diabetes mellitus: impact on gut microbiota and systemic inflammation. Li J, Lu H, Wu H, Huang S, Chen L, Gui Q, Zhou W, Yang Y, Wu Y, Zhang H, Zhang Q, Yang Y. Aging (Albany NY) 12 25956-25980 (2020)
  15. Crystal structure of lipid A disaccharide synthase LpxB from Escherichia coli. Bohl HO, Shi K, Lee JK, Aihara H. Nat Commun 9 377 (2018)
  16. A continuous fluorescent enzyme assay for early steps of lipid A biosynthesis. Jenkins RJ, Dotson GD. Anal Biochem 425 21-27 (2012)
  17. Discovery of dual-activity small-molecule ligands of Pseudomonas aeruginosa LpxA and LpxD using SPR and X-ray crystallography. Kroeck KG, Sacco MD, Smith EW, Zhang X, Shoun D, Akhtar A, Darch SE, Cohen F, Andrews LD, Knox JE, Chen Y. Sci Rep 9 15450 (2019)
  18. Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors Using Pharmacophore-Based Approach. Bhaskar BV, Babu TMC, Rammohan A, Zheng GY, Zyryanov GV, Gu W. Biomolecules 10 E266 (2020)
  19. A high-throughput-compatible fluorescence anisotropy-based assay for competitive inhibitors of Escherichia coli UDP-N-acetylglucosamine acyltransferase (LpxA). Shapiro AB, Ross PL, Gao N, Livchak S, Kern G, Yang W, Andrews B, Thresher J. J Biomol Screen 18 341-347 (2013)
  20. Malonyl-acyl carrier protein decarboxylase activity promotes fatty acid and cell envelope biosynthesis in Proteobacteria. Whaley SG, Radka CD, Subramanian C, Frank MW, Rock CO. J Biol Chem 297 101434 (2021)
  21. Essential Genes of Vibrio anguillarum and Other Vibrio spp. Guide the Development of New Drugs and Vaccines. Bekaert M, Goffin N, McMillan S, Desbois AP. Front Microbiol 12 755801 (2021)
  22. Pathway Driven Target Selection in Klebsiella pneumoniae: Insights Into Carbapenem Exposure. Serral F, Pardo AM, Sosa E, Palomino MM, Nicolás MF, Turjanski AG, Ramos PIP, Fernández Do Porto D. Front Cell Infect Microbiol 12 773405 (2022)
  23. Historical Article Profile of Christian R. H. Raetz. Zagorski N. Proc Natl Acad Sci U S A 104 17252-17254 (2007)
  24. Computer-Based Identification of Potential Druggable Targets in Multidrug-Resistant Acinetobacter baumannii: A Combined In Silico, In Vitro and In Vivo Study. Badie OH, Basyony AF, Samir R. Microorganisms 10 1973 (2022)
  25. Essential Paralogous Proteins as Potential Antibiotic Multitargets in Escherichia coli. Hardy CD. Microbiol Spectr 10 e0204322 (2022)
  26. Identification and prioritization of potential therapeutic molecules against LpxA from Acinetobacter baumannii - A computational study. Khan RJ, Singh E, Jha RK, Kumar A, Bhati SK, Zia MP, Jain M, Singh RP, Muthukumaran J, Singh AK. Curr Res Struct Biol 5 100096 (2023)


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