4bky
Crystal structure of unphosphorylated Maternal Embryonic Leucine zipper Kinase (MELK) in complex with pyrrolopyrazole inhibitor
Structural highlights
DiseaseMELK_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. FunctionMELK_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 upregulated in several types of tumor, including breast, prostate and brain tumors. Its expression is generally associated with cell survival, cell proliferation and resistance to apoptosis. Therefore, the potential of MELK inhibitors as therapeutic agents is recently attracting considerable interest. Here we report the first structures of MELK in complex with AMP-PNP and with nanomolar inhibitors. Our studies shed some light on the role of MELK UBA domain, provide a characterization of the kinase active site and identify key residues for achieving high potency, laying the groundwork for structure-based drug design efforts. Structural insight into Maternal Embryonic Leucine zipper Kinase (MELK) conformation and inhibition towards structure-based drug design.,Canevari G, Re Depaolini S, Cucchi U, Bertrand JA, Casale E, Perrera C, Forte B, Carpinelli P, Felder ER Biochemistry. 2013 Aug 5. PMID:23914841[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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