Journal:JBIC:2

Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß

G. Atilla-Gocumen, L. Di Costanzo, E. Meggers ^[1]

Molecular Tour
A crystal structure of an organometallic half-sandwich ruthenium complex bound to the protein kinase glycogen synthase kinase 3ß (GSK-3ß) has been determined (PDB entry 3m1s) and reveals that the inhibitor binds to the ATP binding site via an induced fit mechanism utlizing several hydrogen bonds and hydrophobic interactions. Importantly, the metal is not involved in any direct interaction with the protein kinase but fulfills a purely structural role. The unique, bulky molecular structure of the half-sandwich complex 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. Although this complex is a conventional ATP-competitive binder, the unique shape of the complex allows novel interactions with the glycine-rich loop which are crucial for binding potency and selectivity. It can be hypothesized that coordination spheres which present other ligands towards the glycine-rich loop might display completely different protein kinase selectivities.

PDB reference: Structure of Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3, 3m1s.

References

1. ↑ Atilla-Gokcumen GE, Di Costanzo L, Meggers E. Structure of anticancer ruthenium half-sandwich complex bound to glycogen synthase kinase 3beta. J Biol Inorg Chem. 2010 Sep 7. PMID:20821241 doi:10.1007/s00775-010-0699-x