4E8Y

Crystal Structure of Burkholderia cenocepacia HldA in Complex with an ATP-competitive Inhibitor

4E8Y の概要

• エントリーDOI: 10.2210/pdb4e8y/pdb
• 関連するPDBエントリー: 4E84 4E8W 4E8Z
• 分子名称: D-beta-D-heptose 7-phosphate kinase, {[2-({[5-(2,6-dimethoxyphenyl)-1,2,4-triazin-3-yl]amino}methyl)-1,3-benzothiazol-5-yl]oxy}acetic acid, 7-O-phosphono-D-glycero-beta-D-manno-heptopyranose, ... (7 entities in total)
• 機能のキーワード: lps-heptose biosynthesis, beta-clasp dimerization region, pfkb carbohydrate kinase, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Burkholderia cenocepacia
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 78180.67

構造登録者

Lee, T.-W.,Verhey, T.B.,Junop, M.S. (登録日: 2012-03-20, 公開日: 2012-12-26, 最終更新日: 2023-09-13)

主引用文献

Lee, T.W.,Verhey, T.B.,Antiperovitch, P.A.,Atamanyuk, D.,Desroy, N.,Oliveira, C.,Denis, A.,Gerusz, V.,Drocourt, E.,Loutet, S.A.,Hamad, M.A.,Stanetty, C.,Andres, S.N.,Sugiman-Marangos, S.,Kosma, P.,Valvano, M.A.,Moreau, F.,Junop, M.S.
Structural-functional studies of Burkholderia cenocepacia D-glycero-beta-D-manno-heptose 7-phosphate kinase (HldA) and characterization of inhibitors with antibiotic adjuvant and antivirulence properties.
J.Med.Chem., 56:1405-1417, 2013

PubMed Abstract: As an essential constituent of the outer membrane of Gram-negative bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural-functional studies of D-glycero-β-D-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia. HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270. Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites. Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors.

PubMed: 23256532
DOI: 10.1021/jm301483h

実験手法

X-RAY DIFFRACTION (2.6 Å)