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PDBsum entry 2vba
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References listed in PDB file
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Key reference
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Title
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Structure-Assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-Acid synthesis.
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Authors
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G.Pappenberger,
T.Schulz-Gasch,
E.Kusznir,
F.Müller,
M.Hennig.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2007,
63,
1208-1216.
[DOI no: ]
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PubMed id
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Abstract
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Fatty-acid synthesis in bacteria is of great interest as a target for the
discovery of antibacterial compounds. The addition of a new acetyl moiety to the
growing fatty-acid chain, an essential step in this process, is catalyzed by
beta-ketoacyl-ACP synthase (KAS). It is inhibited by natural antibiotics such as
cerulenin and thiolactomycin; however, these lack the requirements for optimal
drug development. Structure-based biophysical screening revealed a novel
synthetic small molecule, 2-phenylamino-4-methyl-5-acetylthiazole, that binds to
Escherichia coli KAS I with a binding constant of 25 microM as determined by
fluorescence titration. A 1.35 A crystal structure of its complex with its
target reveals noncovalent interactions with the active-site Cys163 and
hydrophobic residues of the fatty-acid binding pocket. The active site is
accessible through an open conformation of the Phe392 side chain and no
conformational changes are induced at the active site upon ligand binding. This
represents a novel binding mode that differs from thiolactomycin or cerulenin
interaction. The structural information on the protein-ligand interaction offers
strategies for further optimization of this low-molecular-weight compound.
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Figure 1.
Figure 1 Structures of cerulenin, thiolactomycin and
2-phenylamino-4-methyl-5-acetylthiazole.
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Figure 6.
Figure 6 Similarity of the aminothiazole compound to
thiolactomycin. Shape-matching superposition of the
aminothiazole compound (red) with thiolactomycin (blue) results
in a high shape Tanimoto score of 0.73 and a colour score of
0.32. The dashed circle indicates the exact superposition of the
S atoms of the two compounds.
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The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2007,
63,
1208-1216)
copyright 2007.
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