Journal:JBIC:2
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| - | A crystal structure of an <scene name='Journal:JBIC:2/Half_sandwich_complex_no_bonds/1'>organometallic half-sandwich ruthenium complex </scene>bound to the protein kinase glycogen synthase kinase 3ß (GSK-3ß) has been determined and reveals that the inhibitor binds to <scene name='Journal:JBIC:2/Atp_binding_site2/ | + | A crystal structure of an <scene name='Journal:JBIC:2/Half_sandwich_complex_no_bonds/1'>organometallic half-sandwich ruthenium complex </scene>bound to the protein kinase glycogen synthase kinase 3ß (GSK-3ß) has been determined and reveals that the inhibitor binds to <scene name='Journal:JBIC:2/Atp_binding_site2/2'>the ATP binding site</scene> via an induced fit mechanism utlizing several <scene name='Journal:JBIC:2/Half_sandwich_complex/3'>hydrogen bonds</scene> and <scene name='Journal:JBIC:2/Half_sandwich_hydrophobic/2'>hydrophobic interactions</scene> (Click: <scene name='Journal:JBIC:2/Half_sandwich_hydrophobic_stic/1'>Additional Hydrophic View</scene>). 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 <scene name='Journal:JBIC:2/Glycine_rich_loop2/1'>the flexible glycine-rich loop</scene>. 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. |
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Revision as of 10:55, 25 August 2010
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Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß
G. Atilla-Gocumen, L. Di Costanzo, E. Meggers
A crystal structure of an bound to the protein kinase glycogen synthase kinase 3ß (GSK-3ß) has been determined and reveals that the inhibitor binds to via an induced fit mechanism utlizing several and (Click: ). 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 . 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.
