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

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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.

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Acknowledgments

We would like to acknowledge the support and assistance of David W. Christianson (University of Pennsylvania) and his group for crystallography. We also thank Heather Gennadios for helpful discussions.

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Author notes

  1. Luigi Di Costanzo

    Present address: RCSB Protein Data Bank, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, NJ, 08854-8087, USA

  2. Eric Meggers

    Present address: Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032, Marburg, Germany

Authors and Affiliations

  1. Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA, 19104, USA

    G. Ekin Atilla-Gokcumen, Luigi Di Costanzo & Eric Meggers

Authors
  1. G. Ekin Atilla-Gokcumen
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  2. Luigi Di Costanzo
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  3. Eric Meggers
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Corresponding author

Correspondence to Eric Meggers.

Additional information

An Interactive 3D Complement page in Proteopedia is available at: http://proteopedia.org/wiki/index.php/Journal:JBIC:2.

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Atilla-Gokcumen, G.E., Di Costanzo, L. & Meggers, E. Structure of anticancer ruthenium half-sandwich complex bound to glycogen synthase kinase 3β. J Biol Inorg Chem 16, 45–50 (2011). https://doi.org/10.1007/s00775-010-0699-x

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  • DOI: https://doi.org/10.1007/s00775-010-0699-x

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