Structural highlights
Function
H7C745_BURPS
Publication Abstract from PubMed
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.
Unraveling the B. pseudomallei Heptokinase WcbL: From Structure to Drug Discovery.,Vivoli M, Isupov MN, Nicholas R, Hill A, Scott AE, Kosma P, Prior JL, Harmer NJ Chem Biol. 2015 Dec 17;22(12):1622-32. doi: 10.1016/j.chembiol.2015.10.015. PMID:26687481[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Vivoli M, Isupov MN, Nicholas R, Hill A, Scott AE, Kosma P, Prior JL, Harmer NJ. 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. PMID:26687481 doi:http://dx.doi.org/10.1016/j.chembiol.2015.10.015
