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@ARTICLE{Schmitz:617569,
      author       = {Schmitz, Maximilian and Kaltheuner, Ines H. and Anand,
                      Kanchan and Düster, Robert and Moecking, Jonas and
                      Monastyrskyi, Andrii and Duckett, Derek R. and Roush,
                      William R. and Geyer, Matthias},
      title        = {{T}he reversible inhibitor {SR}-4835 binds {C}dk12/cyclin
                      {K} in a noncanonical {G}-loop conformation},
      journal      = {Biologist},
      volume       = {300},
      number       = {1},
      issn         = {0021-9258},
      address      = {Bethesda, MD},
      publisher    = {American Soc. for Biochemistry and Molecular Biology},
      reportid     = {PUBDB-2024-06886},
      pages        = {105501},
      year         = {2024},
      note         = {ISSN 0021-9258 not unique: **2 hits**.},
      abstract     = {Inhibition of cyclin-dependent kinases (CDKs) has evolved
                      as an emerging anticancer strategy. In addition to the cell
                      cycle-regulating CDKs, the transcriptional kinases Cdk12 and
                      Cdk13 have become the focus of interest as they mediate a
                      variety of functions, including the transition from
                      transcription initiation to elongation and termination,
                      precursor mRNA splicing, and intronic polyadenylation. Here,
                      we determine the crystal structure of the small molecular
                      inhibitor SR-4835 bound to the Cdk12/cyclin K complex at
                      2.68 Å resolution. The compound’s benzimidazole moiety is
                      embedded in a unique hydrogen bond network mediated by the
                      kinase hinge region with flanking hydroxy groups of the Y815
                      and D819 side chains. Whereas the SR-4835 head group targets
                      the adenine-binding pocket, the kinase’s glycine-rich loop
                      is shifted down toward the activation loop. Additionally,
                      the αC-helix adopts an inward conformation, and the
                      phosphorylated T-loop threonine interacts with all three
                      canonical arginines, a hallmark of CDK activation that is
                      altered in Cdk12 and Cdk13. Dose-response inhibition
                      measurements with recombinant CMGC kinases show that SR-4835
                      is highly specific for Cdk12 and Cdk13 following a 10-fold
                      lower potency for Cdk10. Whereas other CDK-targeting
                      compounds exhibit tighter binding affinities and higher
                      potencies for kinase inhibition, SR-4835 can be considered a
                      selective transcription elongation antagonist. Our results
                      provide the basis for a rational improvement of SR-4835
                      toward Cdk12 inhibition and a gain in selectivity over other
                      transcription regulating CDKs.},
      cin          = {EMBL-User},
      ddc          = {610},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3) / DFG project
                      G:(GEPRIS)390873048 - EXC 2151: ImmunoSensation2 - the
                      immune sensory system (390873048)},
      pid          = {G:(DE-HGF)POF4-6G3 / G:(GEPRIS)390873048},
      experiment   = {EXP:(DE-H253)P-P14-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38016516},
      UT           = {WOS:001407200700001},
      doi          = {10.1016/j.jbc.2023.105501},
      url          = {https://bib-pubdb1.desy.de/record/617569},
}