3TWD

glmuC1 in complex with an antibacterial inhibitor

3TWD の概要

• エントリーDOI: 10.2210/pdb3twd/pdb
• 分子名称: Bifunctional protein glmU, SULFATE ION, 4-({5-[(4-aminophenyl)(phenyl)sulfamoyl]-2,4-dimethoxyphenyl}amino)-4-oxobutanoic acid, ... (4 entities in total)
• 機能のキーワード: acetyl transferase, uridyl transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Escherichia coli
• 細胞内の位置: Cytoplasm: P0ACC7
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48190.50

構造登録者

Lahiri, S.,Otterbein, L. (登録日: 2011-09-21, 公開日: 2011-10-19, 最終更新日: 2024-02-28)

主引用文献

Buurman, E.T.,Andrews, B.,Gao, N.,Hu, J.,Keating, T.A.,Lahiri, S.,Otterbein, L.R.,Patten, A.D.,Stokes, S.S.,Shapiro, A.B.
In Vitro Validation of Acetyltransferase Activity of GlmU as an Antibacterial Target in Haemophilus influenzae.
J.Biol.Chem., 286:40734-40742, 2011

PubMed Abstract: GlmU is a bifunctional enzyme that is essential for bacterial growth, converting D-glucosamine 1-phosphate into UDP-GlcNAc via acetylation and subsequent uridyl transfer. A biochemical screen of AstraZeneca's compound library using GlmU of Escherichia coli identified novel sulfonamide inhibitors of the acetyltransferase reaction. Steady-state kinetics, ligand-observe NMR, isothermal titration calorimetry, and x-ray crystallography showed that the inhibitors were competitive with acetyl-CoA substrate. Iterative chemistry efforts improved biochemical potency against gram-negative isozymes 300-fold and afforded antimicrobial activity against a strain of Haemophilus influenzae lacking its major efflux pump. Inhibition of precursor incorporation into bacterial macromolecules was consistent with the antimicrobial activity being caused by disruption of peptidoglycan and fatty acid biosyntheses. Isolation and characterization of two different resistant mutant strains identified the GlmU acetyltransferase domain as the molecular target. These data, along with x-ray co-crystal structures, confirmed the binding mode of the inhibitors and explained their relative lack of potency against gram-positive GlmU isozymes. This is the first example of antimicrobial compounds mediating their growth inhibitory effects specifically via GlmU.

PubMed: 21984832
DOI: 10.1074/jbc.M111.274068

実験手法

X-RAY DIFFRACTION (1.9 Å)