6GVX

Crystal structure of Maternal Embryonic Leucine Zipper Kinase (MELK) in complex with dorsomorphin (Compound C)

Summary for 6GVX

• Entry DOI: 10.2210/pdb6gvx/pdb
• Descriptor: Maternal embryonic leucine zipper kinase, 1,2-ETHANEDIOL, 6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine, ... (4 entities in total)
• Functional Keywords: dorsomorphin, melk, inhibitor, cancer, oncoprotein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 80369.31

Authors

Golik, P.,Rembacz, K.P.,Zrubek, K.,Romanowska, M.,Bugusz, J.,Wladyka, B.,Dubin, G. (deposition date: 2018-06-21, release date: 2019-05-29, Last modification date: 2024-01-17)

Primary citation

Rembacz, K.P.,Zrubek, K.M.,Golik, P.,Michalik, K.,Bogusz, J.,Wladyka, B.,Romanowska, M.,Dubin, G.
Crystal structure of Maternal Embryonic Leucine Zipper Kinase (MELK) in complex with dorsomorphin (Compound C).
Arch.Biochem.Biophys., 671:1-7, 2019

PubMed Abstract: Maternal Embryonic Leucine Zipper Kinase (MELK) is overexpressed in various tumors which has been convincingly linked to tumor cell survival. As such, MELK became an interesting target for pharmacological intervention. In this study we present the crystal structure of MELK in complex with dorsomorphin, an inhibitor of VEGFR and AMPK. By defining the mechanistic details of ligand recognition we identify a key residue (Cys89) at the hinge region of MELK responsible for positioning of the ligand at the catalytic pocket. This conclusion is supported by kinetic characterization of Cys89 mutants which show decreased affinity towards both ATP and dorsomorphin. The detailed binding mode of dorsomorphin characterized in this study defines a minimal requirement for MELK ligands, a valuable information for future rational design of inhibitors based on entirely new scaffolds.

PubMed: 31108049
DOI: 10.1016/j.abb.2019.05.014

Experimental method

X-RAY DIFFRACTION (2.24 Å)