Unraveling the B. pseudomallei Heptokinase WcbL: From Structure to Drug Discovery

Chem Biol. 2015 Dec 17;22(12):1622-32. doi: 10.1016/j.chembiol.2015.10.015.


Gram-negative bacteria utilize heptoses as part of their repertoire of extracellular polysaccharide virulence determinants. Disruption of heptose biosynthesis offers an attractive target for novel antimicrobials. A critical step in the synthesis of heptoses is their 1-O phosphorylation, mediated by kinases such as HldE or WcbL. Here, we present the structure of WcbL from Burkholderia pseudomallei. We report that WcbL operates through a sequential ordered Bi-Bi mechanism, loading the heptose first and then ATP. We show that dimeric WcbL binds ATP anti-cooperatively in the absence of heptose, and cooperatively in its presence. Modeling of WcbL suggests that heptose binding causes an elegant switch in the hydrogen-bonding network, facilitating the binding of a second ATP molecule. Finally, we screened a library of drug-like fragments, identifying hits that potently inhibit WcbL. Our results provide a novel mechanism for control of substrate binding and emphasize WcbL as an attractive anti-microbial target for Gram-negative bacteria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Burkholderia pseudomallei / enzymology*
  • Calorimetry, Differential Scanning
  • Computer Simulation
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Heptoses / chemistry
  • Models, Molecular
  • Phosphotransferases / chemistry*
  • Phosphotransferases / metabolism
  • Protein Structure, Tertiary
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*


  • Heptoses
  • Small Molecule Libraries
  • Phosphotransferases

Associated data

  • PDB/4USK
  • PDB/4USM
  • PDB/4UT4
  • PDB/4UTG