4umu

Structure of MELK in complex with inhibitors

spinqualitylabelsall models 4umu, resolution 2.02Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4umu is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 0V0 Related: 4ump, 4umq, 4umr, 4umt Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Publication Abstract from PubMed A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK. Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.,Johnson CN, Adelinet C, Berdini V, Beke L, Bonnet P, Brehmer D, Calo F, Coyle JE, Day PJ, Frederickson M, Freyne EJ, Gilissen RA, Hamlett CC, Howard S, Meerpoel L, Mevellec L, McMenamin R, Pasquier E, Patel S, Rees DC, Linders JT ACS Med Chem Lett. 2014 May 23;6(1):31-6. doi: 10.1021/ml5001273. eCollection, 2015 Jan 8. PMID:25589926 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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