Journal:JBIC:2

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[[Image: 3dzy2.png|420px|left|thumb| Human PPARγ bound to RXRα and PPRE DNA strand, [[3dzy]]]]
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<applet load="" size="600" color="" frame="true" spin="on" Scene ="" align="right" caption="Crystal Structure of Glycogen Synthase Kinase 3ß bound to Anticancer Ruthenium Complex "/>
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{{STRUCTURE_3dzy| right| PDB=3dzy | SCENE=Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/1 |CAPTION= Crystal Structure of Human PPARγ, [[3dzy]] }}
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===Structure of Anticancer Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3ß===
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The [[Peroxisome Proliferator-Activated Receptors]] (PPAR) α, δ, and γ are members of the nuclear receptor family. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of environmental and dietary stimuli, acting as transcription factors to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating [http://en.wikipedia.org/wiki/Hyperlipidemia hypolipidemia] and [http://en.wikipedia.org/wiki/Diabetes diabetes] among other diseases.<ref>PMID:15860251</ref>
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<big>G. Atilla-Gocumen, L. Di Costanzo, E. Meggers</big>
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&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;A crystal structure of an organometallic half-sandwich ruthenium complex bound to the protein kinase glycogen synthase kinase 3ß (GSK-3ß) has been determined and reveals the binding in the ATP binding site via an induced fit mechanism. 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.
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==Biological Role==
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[[Image: PPAR_Mechanism.png|400px|left|thumb| PPAR Mechanism of Action in the Human Body]]
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Transcription of individual genes in eukaryotic cells is controlled very precisely at a number of different levels. One key level is the binding of specific [[DNA]] binding transcriptional factors such as nuclear receptors, to facilitate RNA polymerase function. Unliganded PPARs form a heterodimer with retinoid X receptor (RXR), specifically RXRα. This heterodimer binds to the Peroxisome Proliferator Response Element (PPRE), a specific DNA sequence present in the promoter region of PPAR-regulated genes. <ref>PMID:11330046</ref> Also associated with this unliganded heterodimer is a co-repressor complex which possesses histone deacetylation activity, enforcing a tight chromatin structure which prevents gene transcription. <ref>PMID:15681609</ref> This co-repressor complex is released upon ligand binding (typical ligands include lipids and eicosanoids), allowing various co-activators and co-activator-associated proteins to be recruited. These protein complexes modulate chromatin remodeling as well as facilitate DNA unwinding and linkage to RNA polymerase II machinery, to begin transcription. Some PPAR related co-activators include CBP (Histone Acetylation), SRC-1,2,3 (Chromatin Acetylation), <ref>pmid:7539101</ref> PGC-1 (Recruit [http://en.wikipedia.org/wiki/Histone_acetyltransferase HAT activities]), PRIC-285,320 (Chromatin Remodeling via Helicase activity)<ref>PMID:11158331</ref>and PIMT (RNA Capping via methyltransferase activity)<ref>PMID:10381882</ref>.
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Revision as of 08:13, 24 August 2010

Crystal Structure of Glycogen Synthase Kinase 3ß bound to Anticancer Ruthenium Complex

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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 organometallic half-sandwich ruthenium complex bound to the protein kinase glycogen synthase kinase 3ß (GSK-3ß) has been determined and reveals the binding in the ATP binding site via an induced fit mechanism. 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.


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