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

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

Arch Biochem Biophys

Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387, Krakow, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland. Electronic address:

Published: August 2019

AI Article Synopsis

Article 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.

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Source
http://dx.doi.org/10.1016/j.abb.2019.05.014DOI Listing

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