2O3Z

X-ray crystal structure of LpxC complexed with 3-heptyloxybenzoate

Summary for 2O3Z

• Entry DOI: 10.2210/pdb2o3z/pdb
• Related: 1P42
• Descriptor: UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, SULFATE ION, ZINC ION, ... (6 entities in total)
• Functional Keywords: lipid a biosynthesis, lipid synthesis, lpxc, 3-heptyloxybenzoate, hydrolase
• Biological source: Aquifex aeolicus
• Total number of polymer chains: 2
• Total formula weight: 63006.26

Authors

Gennadios, H.A.,Whittington, D.A.,Christianson, D.W. (deposition date: 2006-12-02, release date: 2007-02-27, Last modification date: 2023-08-30)

Primary citation

Shin, H.,Gennadios, H.A.,Whittington, D.A.,Christianson, D.W.
Amphipathic benzoic acid derivatives: synthesis and binding in the hydrophobic tunnel of the zinc deacetylase LpxC.
Bioorg.Med.Chem., 15:2617-2623, 2007

PubMed Abstract: The first committed step in lipid A biosynthesis is catalyzed by uridine diphosphate-(3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC), a zinc-dependent deacetylase, and inhibitors of LpxC may be useful in the development of antibacterial agents targeting a broad spectrum of Gram-negative bacteria. Here, we report the design of amphipathic benzoic acid derivatives that bind in the hydrophobic tunnel in the active site of LpxC. The hydrophobic tunnel accounts for the specificity of LpxC toward substrates and substrate analogues bearing a 3-O-myristoyl substituent. Simple benzoic acid derivatives bearing an aliphatic 'tail' bind in the hydrophobic tunnel with micromolar affinity despite the lack of a glucosamine ring like that of the substrate. However, although these benzoic acid derivatives each contain a negatively charged carboxylate 'warhead' intended to coordinate to the active site zinc ion, the 2.25A resolution X-ray crystal structure of LpxC complexed with 3-(heptyloxy)benzoate reveals 'backward' binding in the hydrophobic tunnel, such that the benzoate moiety does not coordinate to zinc. Instead, it binds at the outer end of the hydrophobic tunnel. Interestingly, these ligands bind with affinities comparable to those measured for more complicated substrate analogue inhibitors containing glucosamine ring analogues and hydroxamate 'warheads' that coordinate to the active site zinc ion. We conclude that the intermolecular interactions in the hydrophobic tunnel dominate enzyme affinity in this series of benzoic acid derivatives.

PubMed: 17296300
DOI: 10.1016/j.bmc.2007.01.044

Experimental method

X-RAY DIFFRACTION (2.25 Å)