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2017 ; 24
(7
): 870-880.e5
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The Ligand Binding Landscape of Diacylglycerol Kinases
#MMPMID28712745
Franks CE
; Campbell ST
; Purow BW
; Harris TE
; Hsu KL
Cell Chem Biol
2017[Jul]; 24
(7
): 870-880.e5
PMID28712745
show ga
Diacylglycerol kinases (DGKs) are integral components of signal transduction
cascades that regulate cell biology through ATP-dependent phosphorylation of the
lipid messenger diacylglycerol. Methods for direct evaluation of DGK activity in
native biological systems are lacking and needed to study isoform-specific
functions of these multidomain lipid kinases. Here, we utilize ATP acyl phosphate
activity-based probes and quantitative mass spectrometry to define, for the first
time, ATP and small-molecule binding motifs of representative members from all
five DGK subtypes. We use chemical proteomics to discover an unusual binding mode
for the DGK? inhibitor, ritanserin, including interactions at the atypical C1
domain distinct from the ATP binding region. Unexpectedly, deconstruction of
ritanserin yielded a fragment compound that blocks DGK? activity through a
conserved binding mode and enhanced selectivity against the kinome. Collectively,
our studies illustrate the power of chemical proteomics to profile protein-small
molecule interactions of lipid kinases for fragment-based lead discovery.
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