4E8Y

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

Summary for 4E8Y

• Entry DOI: 10.2210/pdb4e8y/pdb
• Related: 4E84 4E8W 4E8Z
• Descriptor: 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)
• Functional Keywords: lps-heptose biosynthesis, beta-clasp dimerization region, pfkb carbohydrate kinase, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Burkholderia cenocepacia
• Total number of polymer chains: 2
• Total formula weight: 78180.67

Authors

Lee, T.-W.,Verhey, T.B.,Junop, M.S. (deposition date: 2012-03-20, release date: 2012-12-26, Last modification date: 2023-09-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)