The Ligand Binding Landscape of Diacylglycerol Kinases

Caroline E. Franks, Sean T. Campbell, Benjamin W. Purow, Thurl E. Harris, Ku Lung Hsu

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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 DGKα 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 DGKα 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.

Original languageEnglish (US)
Pages (from-to)870-880.e5
JournalCell Chemical Biology
Issue number7
StatePublished - Jul 20 2017
Externally publishedYes


  • activity-based protein profiling
  • cancer immunotherapy
  • chemical proteomics
  • diacylglycerol kinase
  • diacylglycerol signaling
  • fragment-based drug discovery
  • ligand deconstruction
  • lipid kinase inhibitors
  • lipid phosphorylation
  • phosphatidic acid signaling

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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