4E1K

GlmU in complex with a Quinazoline Compound

4E1K の概要

• エントリーDOI: 10.2210/pdb4e1k/pdb
• 分子名称: Bifunctional protein GlmU, SULFATE ION, TETRAETHYLENE GLYCOL, ... (5 entities in total)
• 機能のキーワード: peptidoglycan synthesis, cell shape, metal-binding, cell wall biogenesis/degradation, multifunctional enzyme, acyltransferase, uridyltransferase, nucleotidyl transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Haemophilus influenzae
• 細胞内の位置: Cytoplasm (By similarity): P43889
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 50214.88

構造登録者

Larsen, N.A.,Doig, P. (登録日: 2012-03-06, 公開日: 2013-05-29, 最終更新日: 2024-02-28)

主引用文献

Larsen, N.A.,Nash, T.J.,Morningstar, M.,Shapiro, A.B.,Joubran, C.,Blackett, C.J.,Patten, A.D.,Boriack-Sjodin, P.A.,Doig, P.
An aminoquinazoline inhibitor of the essential bacterial cell wall synthetic enzyme GlmU has a unique non-protein-kinase-like binding mode.
Biochem.J., 446:405-413, 2012

PubMed Abstract: GlmU is a bifunctional enzyme with acetyltransferase and uridyltransferase activities, and is essential for the biosynthesis of the bacterial cell wall. Inhibition results in a loss of cell viability. GlmU is therefore considered a potential target for novel antibacterial agents. A HTS (high-throughput screen) identified a series of aminoquinazolines with submicromolar potency against the uridyltransferase reaction. Biochemical and biophysical characterization showed competition with UTP binding. We determined the crystal structure of a representative aminoquinazoline bound to the Haemophilus influenzae isoenzyme at a resolution of 2.0 Å. The inhibitor occupies part of the UTP site, skirts the outer perimeter of the GlcNAc1-P (N-acetylglucosamine-1-phosphate) pocket and anchors a hydrophobic moiety into a lipophilic pocket. Our SAR (structure-activity relationship) analysis shows that all of these interactions are essential for inhibitory activity in this series. The crystal structure suggests that the compound would block binding of UTP and lock GlmU in an apo-enzyme-like conformation, thus interfering with its enzymatic activity. Our lead generation effort provides ample scope for further optimization of these compounds for antibacterial drug discovery.

PubMed: 22721802
DOI: 10.1042/BJ20120596

実験手法

X-RAY DIFFRACTION (2 Å)