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

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. PMID:26687481 | PMC:PMC4691232 | DOI:10.1016/j.chembiol.2015.10.015

Source: Chemistry and Biology - December 22, 2015 Category: Chemistry Authors: Mirella Vivoli Michail N Isupov Rebecca Nicholas Andrew Hill Andrew E Scott Paul Kosma Joann L Prior Nicholas J Harmer Source Type: research