Structure of anticancer ruthenium half-sandwich complex bound to glycogen synthase kinase 3β

The 3.15-angstrom-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 3 beta (GSK-3 beta) is reported and the binding is compared with the GSK-3 beta binding of staurosporine and other organic inhibitors. The structure reveals a close packing of the organometallic inhibitor in the ATP binding site of GSK-3 beta 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 Nand C-terminal lobes and to interact tightly with the flexible glycine-rich loop, which is uncommon for the interaction of GSK-3 beta with organic inhibitors.