chir-090 has been researched along with morpholine* in 1 studies
1 other study(ies) available for chir-090 and morpholine
Article | Year |
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Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding.
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. Topics: Acetylene; Acetylesterase; Amino Acid Sequence; Anti-Bacterial Agents; Bacterial Proteins; Biphenyl Compounds; Catalysis; Conserved Sequence; Enzyme Inhibitors; Hydroxamic Acids; Ligands; Models, Molecular; Molecular Sequence Data; Morpholines; Mutation; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Protein Structure, Tertiary; Sequence Alignment; Substrate Specificity; Threonine; Time Factors | 2007 |