Structural basis for small molecule targeting of Doublecortin Like Kinase 1 with DCLK1-IN-1
- Details
- Publication Year 2021-09-20,Volume 4,Issue #1,Page 1105
- Journal Title
- Communications Biology
- Abstract
- Doublecortin-like kinase 1 (DCLK1) is an understudied bi-functional kinase with a proven role in tumour growth and development. However, the presence of tissue-specific spliced DCLK1 isoforms with distinct biological functions have challenged the development of effective strategies to understand the role of DCLK1 in oncogenesis. Recently, DCLK1-IN-1 was reported as a highly selective DCLK1 inhibitor, a powerful tool to dissect DCLK1 biological functions. Here, we report the crystal structures of DCLK1 kinase domain in complex with DCLK1-IN-1 and its precursors. Combined, our data rationalises the structure-activity relationship that informed the development of DCLK1-IN-1 and provides the basis for the high selectivity of DCLK1-IN-1, with DCLK1-IN-1 inducing a drastic conformational change of the ATP binding site. 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.
- Publisher
- NPG
- Research Division(s)
- Chemical Biology
- PubMed ID
- 34545159
- Publisher's Version
- https://doi.org/10.1038/s42003-021-02631-y
- Open Access at Publisher's Site
https://doi.org/10.1038/s42003-021-02631-y- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-10-12 07:30:12
Last Modified: 2021-10-19 11:18:00