7KX6

Crystal structure of DCLK1-KD in complex with XMD8-85

Summary for 7KX6

• Entry DOI: 10.2210/pdb7kx6/pdb
• Descriptor: Serine/threonine-protein kinase DCLK1, 2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one (3 entities in total)
• Functional Keywords: kinase, doublecortin-like, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 63518.57

Authors

Patel, O.,Lucet, I. (deposition date: 2020-12-03, release date: 2021-09-22, Last modification date: 2023-10-18)

Primary citation

Patel, O.,Roy, M.J.,Kropp, A.,Hardy, J.M.,Dai, W.,Lucet, I.S.
Structural basis for small molecule targeting of Doublecortin Like Kinase 1 with DCLK1-IN-1.
Commun Biol, 4:1105-1105, 2021

PubMed 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.

PubMed: 34545159
DOI: 10.1038/s42003-021-02631-y

Experimental method

X-RAY DIFFRACTION (2.5 Å)