2jt2

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

Overview

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.

About this Structure

2JT2 is a Single protein structure of sequence from Aquifex aeolicus with and as ligands. Full crystallographic information is available from OCA.

Reference

Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding., Barb AW, Jiang L, Raetz CR, Zhou P, Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18433-8. Epub 2007 Nov 19. PMID:18025458

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