2JT2

Solution Structure of the Aquifex aeolicus LpxC- CHIR-090 complex

Summary for 2JT2

• Entry DOI: 10.2210/pdb2jt2/pdb
• Descriptor: UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, ZINC ION, N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}-4-{[4-(morpholin-4-ylmethyl)phenyl]ethynyl}benzamide (3 entities in total)
• Functional Keywords: antibiotic, lipid a, hydroxamate, chir-090, hydrolase, lipid a biosynthesis, lipid synthesis
• Biological source: Aquifex aeolicus
• Total number of polymer chains: 1
• Total formula weight: 31817.76

Authors

Barb, A.W.,Jiang, L.,Raetz, C.R.H.,Zhou, P. (deposition date: 2007-07-18, release date: 2007-12-04, Last modification date: 2024-05-29)

Primary citation

Barb, A.W.,Jiang, L.,Raetz, C.R.,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.Usa, 104:18433-18438, 2007

PubMed Abstract: 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.

PubMed: 18025458
DOI: 10.1073/pnas.0709412104

Experimental method

SOLUTION NMR