title: Structure of anticancer ruthenium half-sandwich complex bound to glycogen synthase kinase 3β.
abstract: The 3.15-Å-resolution crystal structure of the R enantiomer of the highly bioactive and antiproliferative half-sandwich ruthenium complex DW12 bound to the ATP binding site of glycogen synthase kinase 3β (GSK-3β) is reported and the binding is compared with the GSK-3β binding of staurosporine and other organic inhibitors. The structure reveals a close packing of the organometallic inhibitor in the ATP binding site of GSK-3β via an induced-fit mechanism. The molecular structure of (R)-DW12 with the CO ligand oriented perpendicular to the pyridocarbazole heterocycle allows the complex to stretch the whole distance sandwiched between the faces of the N- and C-terminal lobes and to interact tightly with the flexible glycine-rich loop, which is uncommon for the interaction of GSK-3β with organic inhibitors.
authors.affiliation: Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104, USA.
authors.forename: G Ekin
authors.initials: GE
authors.lastname: Atilla-Gokcumen
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Costanzo
authors.forename: Eric
authors.initials: E
authors.lastname: Meggers
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D000071679:Glycogen Synthase Kinase 3 beta; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D012428:Ruthenium; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
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