4UTG

Burkholderia pseudomallei heptokinase WcbL,AMPPNP (ATP analogue) complex.

Summary for 4UTG

• Entry DOI: 10.2210/pdb4utg/pdb
• Related: 4UT4
• Descriptor: SUGAR KINASE, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: transferase, capsular polysaccharide, drug discovery, heptopyranose
• Biological source: BURKHOLDERIA PSEUDOMALLEI K96243
• Total number of polymer chains: 2
• Total formula weight: 77021.50

Authors

Vivoli, M.,Isupov, M.N.,Nicholas, R.,Hill, A.,Scott, A.,Kosma, P.,Prior, J.,Harmer, N.J. (deposition date: 2014-07-21, release date: 2016-01-13, Last modification date: 2024-05-08)

Primary citation

Vivoli, M.,Isupov, M.N.,Nicholas, R.,Hill, A.,Scott, A.E.,Kosma, P.,Prior, J.L.,Harmer, N.J.
Unraveling the B.Pseudomallei Heptokinase Wcbl: From Structure to Drug Discovery.
Chem.Biol., 22:1622-, 2015

PubMed Abstract: 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.

PubMed: 26687481
DOI: 10.1016/J.CHEMBIOL.2015.10.015

Experimental method

X-RAY DIFFRACTION (1.93 Å)