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Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding.

Publication ,  Journal Article
Barb, AW; Jiang, L; Raetz, CRH; Zhou, P
Published in: Proc Natl Acad Sci U S A
November 20, 2007

The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising antibiotic target. CHIR-090, the most potent LpxC inhibitor discovered to date, displays two-step time-dependent inhibition and kills a wide range of Gram-negative pathogens as effectively as ciprofloxacin or tobramycin. In this study, we report the solution structure of the LpxC-CHIR-090 complex. CHIR-090 exploits conserved features of LpxC that are critical for catalysis, including the hydrophobic passage and essential active-site residues. CHIR-090 is adjacent to, but does not occupy, the UDP-binding pocket of LpxC, suggesting that a fragment-based approach may facilitate further optimization of LpxC inhibitors. Additionally, we identified key residues in the Insert II hydrophobic passage that modulate time-dependent inhibition and CHIR-090 resistance. CHIR-090 shares a similar, although previously unrecognized, chemical scaffold with other small-molecule antibiotics such as L-161,240 targeting LpxC, and provides a template for understanding the binding mode of these inhibitors. Consistent with this model, we provide evidence that L-161,240 also occupies the hydrophobic passage.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

November 20, 2007

Volume

104

Issue

47

Start / End Page

18433 / 18438

Location

United States

Related Subject Headings

  • Time Factors
  • Threonine
  • Substrate Specificity
  • Sequence Alignment
  • Protein Structure, Tertiary
  • Protein Binding
  • Nuclear Magnetic Resonance, Biomolecular
  • Mutation
  • Morpholines
  • Molecular Sequence Data
 

Citation

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Barb, A. W., Jiang, L., Raetz, C. R. H., & Zhou, P. (2007). Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding. Proc Natl Acad Sci U S A, 104(47), 18433–18438. https://doi.org/10.1073/pnas.0709412104
Barb, Adam W., Ling Jiang, Christian R. H. Raetz, and Pei Zhou. “Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding.Proc Natl Acad Sci U S A 104, no. 47 (November 20, 2007): 18433–38. https://doi.org/10.1073/pnas.0709412104.
Barb AW, Jiang L, Raetz CRH, Zhou P. Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18433–8.
Barb, Adam W., et al. “Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding.Proc Natl Acad Sci U S A, vol. 104, no. 47, Nov. 2007, pp. 18433–38. Pubmed, doi:10.1073/pnas.0709412104.
Barb AW, Jiang L, Raetz CRH, Zhou P. Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18433–18438.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

November 20, 2007

Volume

104

Issue

47

Start / End Page

18433 / 18438

Location

United States

Related Subject Headings

  • Time Factors
  • Threonine
  • Substrate Specificity
  • Sequence Alignment
  • Protein Structure, Tertiary
  • Protein Binding
  • Nuclear Magnetic Resonance, Biomolecular
  • Mutation
  • Morpholines
  • Molecular Sequence Data