Engineering Peptide Inhibitors To Overcome PDZ Binding Promiscuity

Authors

  • Lars Vouilleme,

    1. Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Hessische Strasse 3–4, 10115 Berlin (Germany), Fax: (+49) 30-450-524942
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    • These authors contributed equally to the work.

  • Patrick R. Cushing,

    1. Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, NH 03755 (USA), Fax: (+1) 603-650-1128
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    • These authors contributed equally to the work.

  • Dr. Rudolf Volkmer,

    1. Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Hessische Strasse 3–4, 10115 Berlin (Germany), Fax: (+49) 30-450-524942
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  • Dr. Dean R. Madden,

    Corresponding author
    1. Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, NH 03755 (USA), Fax: (+1) 603-650-1128
    • Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, NH 03755 (USA), Fax: (+1) 603-650-1128
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  • Dr. Prisca Boisguerin

    Corresponding author
    1. Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Hessische Strasse 3–4, 10115 Berlin (Germany), Fax: (+49) 30-450-524942
    • Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Hessische Strasse 3–4, 10115 Berlin (Germany), Fax: (+49) 30-450-524942
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  • This work was supported in part by grants from the NIH (Grants R01-DK075309 from NIDDK, T32-GM008704 from NIGMS, and P20-RR018787 from the NCRR), the Cystic Fibrosis Foundation (MADDEN06P0 and STANTO97R0), and the Deutsche Forschungsgemeinschaft (DFG Grant VO 885/3 2). L.V. is supported by a financial grant of the Mukoviszidose e.V. (S05/08), the German cystic fibrosis association, and P.B. by a Charité-Habilitationsstipendium. We thank Dr. J. Bodwell for plate-reader access and J. Piro for protein-purification assistance.

Abstract

original image

Design von Inhibitoren: PDZ-Domänen sind konservierte Module, die die Lokalisation und Aktivität von Protein-Effektoren regulieren. Fünf promiskuitive PDZ-Domänen wurden mit einem integrierten Ansatz bestehend aus Peptidbibliotheken-Screening-Techniken und Fluoreszenzpolarisationsmessungen analysiert. Durch die Kombination beider Methoden konnte ein hochspezifischer Inhibitor (iCAL3610=ANSRWPTSII) für eine dieser PDZ-Domänen entwickelt werden.

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