2GO4

Crystal structure of Aquifex aeolicus LpxC complexed with TU-514

2GO4 の概要

• エントリーDOI: 10.2210/pdb2go4/pdb
• 分子名称: UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, ZINC ION, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: lpxc-inhibitor complex, hydrolase
• 由来する生物種: Aquifex aeolicus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62203.37

構造登録者

Gennadios, H.A.,Whittington, D.A.,Li, X.,Fierke, C.A.,Christianson, D.W. (登録日: 2006-04-12, 公開日: 2006-07-04, 最終更新日: 2023-08-30)

主引用文献

Gennadios, H.A.,Whittington, D.A.,Li, X.,Fierke, C.A.,Christianson, D.W.
Mechanistic Inferences from the Binding of Ligands to LpxC, a Metal-Dependent Deacetylase
Biochemistry, 45:7940-7948, 2006

PubMed Abstract: The metal-dependent deacetylase LpxC catalyzes the first committed step of lipid A biosynthesis in Gram-negative bacteria. Accordingly, LpxC is an attractive target for the development of inhibitors that may serve as potential new antibiotics for the treatment of Gram-negative bacterial infections. Here, we report the 2.7 A resolution X-ray crystal structure of LpxC complexed with the substrate analogue inhibitor TU-514 and the 2.0 A resolution structure of LpxC complexed with imidazole. The X-ray crystal structure of LpxC complexed with TU-514 allows for a detailed examination of the coordination geometry of the catalytic zinc ion and other enzyme-inhibitor interactions in the active site. The hydroxamate group of TU-514 forms a bidentate chelate complex with the zinc ion and makes hydrogen bond interactions with conserved active site residues E78, H265, and T191. The inhibitor C-4 hydroxyl group makes direct hydrogen bond interactions with E197 and H58. Finally, the C-3 myristate moiety of the inhibitor binds in the hydrophobic tunnel of the active site. These intermolecular interactions provide a foundation for understanding structural aspects of enzyme-substrate and enzyme-inhibitor affinity. Comparison of the TU-514 complex with cacodylate and imidazole complexes suggests a possible substrate diphosphate binding site and highlights residues that may stabilize the tetrahedral intermediate and its flanking transition states in catalysis. Evidence of a catalytic zinc ion in the native zinc enzyme coordinated by H79, H238, D242, and two water molecules with square pyramidal geometry is also presented. These results suggest that the native state of this metallohydrolase may contain a pentacoordinate zinc ion, which contrasts with the native states of archetypical zinc hydrolases such as thermolysin and carboxypeptidase A.

PubMed: 16800620
DOI: 10.1021/bi060823m

実験手法

X-RAY DIFFRACTION (2.7 Å)