6gvx
From Proteopedia
Crystal structure of Maternal Embryonic Leucine Zipper Kinase (MELK) in complex with dorsomorphin (Compound C)
Structural highlights
Disease[MELK_HUMAN] Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation. Function[MELK_HUMAN] Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedMaternal 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. Crystal structure of Maternal Embryonic Leucine Zipper Kinase (MELK) in complex with dorsomorphin (Compound C).,Rembacz KP, Zrubek KM, Golik P, Michalik K, Bogusz J, Wladyka B, Romanowska M, Dubin G Arch Biochem Biophys. 2019 May 17. pii: S0003-9861(18)31040-3. doi:, 10.1016/j.abb.2019.05.014. PMID:31108049[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Bugusz, J | Dubin, G | Golik, P | Rembacz, K P | Romanowska, M | Wladyka, B | Zrubek, K | Cancer | Dorsomorphin | Inhibitor | Melk | Oncoprotein
