PDBsum entry 2vba

Transferase

PDB id: 2vba

Contents

Protein chains

404 a.a. *

Ligands

P4T

Waters ×2431

* Residue conservation analysis

PDB id:

2vba

Name:

Transferase

Title:

Beta-ketoacyl-acp synthase i (kas) from e. Coli with bound amino- thiazole inhibitor

Structure:

3-oxoacyl-[acyl-carrier-protein] synthase 1. Chain: a, b, c, d. Synonym: beta-ketoacyl-acp synthase i, 3-oxoacyl-[acyl-carrier- protein] synthase i, kas i. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.36Å R-factor: 0.121 R-free: 0.151

Authors:

G.Pappenberger,T.Schulz-Gasch,J.Bailly,M.Hennig

Key ref:

G.Pappenberger et al. (2007). Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis. Acta Crystallogr D Biol Crystallogr, 63, 1208-1216. PubMed id: 18084068 DOI: 10.1107/S0907444907049852

Date:

06-Sep-07 Release date: 25-Dec-07

Protein chains

P0A953  (FABB_ECOLI) -  3-oxoacyl-[acyl-carrier-protein] synthase 1 from Escherichia coli (strain K12)

Seq: 406 a.a.

Struc: 404 a.a.

Enzyme reactions

• Enzyme class: E.C.2.3.1.41 - beta-ketoacyl-[acyl-carrier-protein] synthase I.
• Reaction: a fatty acyl-[ACP] + malonyl-[ACP] + H⁺ = a 3-oxoacyl-[ACP] + holo- [ACP] + CO2

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

DOI no: 10.1107/S0907444907049852

Acta Crystallogr D Biol Crystallogr 63:1208-1216 (2007)

PubMed id: 18084068

Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis.

G.Pappenberger, T.Schulz-Gasch, E.Kusznir, F.Müller, M.Hennig.

ABSTRACT

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.

Selected figure(s)

Figure 1.
Figure 1 Structures of cerulenin, thiolactomycin and 2-phenylamino-4-methyl-5-acetylthiazole.

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.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2007, 63, 1208-1216) copyright 2007.

Figures were selected by an automated process.