title: Structural insight into maternal embryonic leucine zipper kinase (MELK) conformation and inhibition toward structure-based drug design.
abstract: Maternal 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 light on the role of the 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.
authors.affiliation: Nerviano Medical Sciences , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Canevari
authors.forename: Stefania
authors.initials: S
authors.lastname: Re Depaolini
authors.forename: Ulisse
authors.initials: U
authors.lastname: Cucchi
authors.forename: Jay A
authors.initials: JA
authors.lastname: Bertrand
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.forename: Claudia
authors.initials: C
authors.lastname: Perrera
authors.forename: Barbara
authors.initials: B
authors.lastname: Forte
authors.forename: Patrizia
authors.initials: P
authors.lastname: Carpinelli
authors.forename: Eduard R
authors.initials: ER
authors.lastname: Felder
mesh_terms: D000266:Adenylyl Imidodiphosphate / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D000266:Adenylyl Imidodiphosphate; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases