Oral Presentation The 47th Lorne Conference on Protein Structure and Function 2022

Structural basis for small molecule targeting of Doublecortin Like Kinase 1 with DCLK1-IN-1 (#2)

Onisha Patel 1 2 , Michael Roy 1 2 , Ashleigh Kropp 1 2 , Joshua Hardy 1 2 , Weiwen Dai 1 2 , Isabelle Lucet 1 2
  1. Chemical Biology, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia

The Doublecortin-like family of kinases are an understudied group of serine/threonine kinases which include three members, DCLK1, DCLK2 and DCLK3. In humans, DCLK1 and DCLK2 are bi-functional proteins classified as Microtubule-Associated Proteins (MAP) and serine/threonine kinases that play a critical role in regulating microtubule assembly. DCLK1, the most studied member of the DCLK family, is upregulated or mutated in a wide range of cancers. Knockdown studies have shown that DCLK1 is functionally important for tumour growth. However, the presence of tissue and development-specific spliced DCLK1 isoforms and the lack of systematic evaluation of their biological function have challenged the development of effective strategies to understand the role of DCLK1 in oncogenesis. Here, we report the crystal structures of the DCLK1 kinase domain in complex with DCLK1-IN-1 and its precursors. Our data provides DCLK1-IN-1 high selectivity for DCLK1, with DCLK1-IN-1 inducing a drastic conformational change of the ATP binding site. In addition, we demonstrate that DCLK1-IN-1 binds DCLK1 long isoforms but does not prevent DCLK1’s Microtubule-Associated Protein (MAP) function. Together, our work provides an invaluable structural platform to further the design of isoform-specific DCLK1 modulators for therapeutic intervention.

  1. Patel O#, Roy MJ, Kropp A, Hardy JM, Dai W, Lucet IS#. Structural basis for small molecule targeting of Doublecortin like kinase 1 with DCLK1-IN-1. Commun Biol 4:1105 (2021). #joint corresponding