2o3z
From Proteopedia
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|PDB= 2o3z |SIZE=350|CAPTION= <scene name='initialview01'>2o3z</scene>, resolution 2.25Å | |PDB= 2o3z |SIZE=350|CAPTION= <scene name='initialview01'>2o3z</scene>, resolution 2.25Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand= | + | |LIGAND= <scene name='pdbligand=AI7:3-(HEPTYLOXY)BENZOIC+ACID'>AI7</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= lpxC, envA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=63363 Aquifex aeolicus]) | |GENE= lpxC, envA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=63363 Aquifex aeolicus]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1p42|1P42]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2o3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2o3z OCA], [http://www.ebi.ac.uk/pdbsum/2o3z PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2o3z RCSB]</span> | ||
}} | }} | ||
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[[Category: Gennadios, H A.]] | [[Category: Gennadios, H A.]] | ||
[[Category: Whittington, D A.]] | [[Category: Whittington, D A.]] | ||
| - | [[Category: AI7]] | ||
| - | [[Category: CL]] | ||
| - | [[Category: SO4]] | ||
| - | [[Category: ZN]] | ||
[[Category: 3-heptyloxybenzoate]] | [[Category: 3-heptyloxybenzoate]] | ||
[[Category: lipid a biosynthesis]] | [[Category: lipid a biosynthesis]] | ||
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[[Category: lpxc]] | [[Category: lpxc]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:12:22 2008'' |
Revision as of 01:12, 31 March 2008
| |||||||
| , resolution 2.25Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , | ||||||
| Gene: | lpxC, envA (Aquifex aeolicus) | ||||||
| Related: | 1P42
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
X-ray crystal structure of LpxC complexed with 3-heptyloxybenzoate
Overview
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.
About this Structure
2O3Z is a Single protein structure of sequence from Aquifex aeolicus. Full crystallographic information is available from OCA.
Reference
Amphipathic benzoic acid derivatives: synthesis and binding in the hydrophobic tunnel of the zinc deacetylase LpxC., Shin H, Gennadios HA, Whittington DA, Christianson DW, Bioorg Med Chem. 2007 Apr 1;15(7):2617-23. Epub 2007 Jan 31. PMID:17296300
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