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Development of Selective RabGGTase Inhibitors and Crystal Structure of a RabGGTase–Inhibitor Complex

Authors

  • Zhong Guo,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, Fax: (+49) 231-133-2399
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    • These authors contributed equally to this work.

  • Yao-Wen Wu,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, Fax: (+49) 231-133-2399
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    • These authors contributed equally to this work.

  • Kui-Thong Tan Dr.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
    2. TU Dortmund, Fachbereich Chemie, 44227 Dortmund, Germany, Fax: (+49) 231-133-2499
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  • Robin S. Bon Dr.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
    2. TU Dortmund, Fachbereich Chemie, 44227 Dortmund, Germany, Fax: (+49) 231-133-2499
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  • Ester Guiu-Rozas Dr.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
    2. TU Dortmund, Fachbereich Chemie, 44227 Dortmund, Germany, Fax: (+49) 231-133-2499
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  • Christine Delon Dr.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, Fax: (+49) 231-133-2399
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  • Uyen T. Nguyen Dipl.-Chem.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, Fax: (+49) 231-133-2399
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  • Stefan Wetzel Dipl.-Chem.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
    2. TU Dortmund, Fachbereich Chemie, 44227 Dortmund, Germany, Fax: (+49) 231-133-2499
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  • Sabine Arndt Dr.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
    2. TU Dortmund, Fachbereich Chemie, 44227 Dortmund, Germany, Fax: (+49) 231-133-2499
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  • Roger S. Goody Prof. Dr.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, Fax: (+49) 231-133-2399
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  • Wulf Blankenfeldt Dr.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, Fax: (+49) 231-133-2399
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  • Kirill Alexandrov Dr.,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, Fax: (+49) 231-133-2399
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  • Herbert Waldmann Prof. Dr.

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
    2. TU Dortmund, Fachbereich Chemie, 44227 Dortmund, Germany, Fax: (+49) 231-133-2499
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  • RabGGTase: Rab geranylgeranyl transferase. We thank the X-ray communities of the Max-Planck-Institut für molekulare Physiologie (Dortmund, Germany) and the Max-Planck-Institut für medizinische Forschung (Heidelberg, Germany) for collecting diffraction data at the Swiss Light Source of the Paul Scherrer Institute (Villigen, Switzerland) and for giving us generous access and support for the station X10SA. K.A. was supported by a Heisenberg Award of the Deutsche Forschungsgemeinschaft (DFG). This work was supported in part by DFG grants to K.A. (grant no.: AL 484/7-2) and to K.A., R.S.G, and H.W. (grant no.: SFB642), and by the Zentrum für Angewandte Chemische Genomik. R.S.B. thanks the Alexander von Humboldt Stiftung for a scholarship.

Abstract

original image

Stopping the transfer: Based on the structure of pepticinnamin E, specific inhibitors of Rab geranylgeranyl transferase (RabGGTase) with activity in cells were developed, and the first crystal structure of the enzyme in complex with an inhibitor is reported (see inhibitor structure and positioning in the active site of the enzyme). The findings may have implications for the chemical-biological study of Rab prenylation and vesicular transport and the involvement of RabGGTase in the establishment of disease.

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