• Open Access

Using Ligand-Mapping Simulations to Design a Ligand Selectively Targeting a Cryptic Surface Pocket of Polo-Like Kinase 1

Authors

  • Yaw Sing Tan,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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    • These authors contributed equally to this work.

  • Dr. Paweł Śledź,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
    2. Present address: Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried (Germany)
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    • These authors contributed equally to this work.

  • Dr. Steffen Lang,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • Christopher J. Stubbs,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • Dr. David R. Spring,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • Prof. Chris Abell,

    Corresponding author
    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
    • Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • Dr. Robert B. Best

    Corresponding author
    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
    • Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • We are grateful for funding from the Agency for Science, Technology and Research (Y.S.T.), the Wellcome Trust, the Gates Cambridge Trust, St. Edmund’s College (P.Ś.) and DAAD (S.L.). R.B.B. is supported by a Royal Society University Research Fellowship. We thank Dr. Marko Hyvönen for assistance with the structural biology, Dr. Chandra Verma for helpful discussions.

Abstract

original image

Ein Verfahren mit expliziter Ligandenkartierung war geeignet, um eine unerkannt gebliebene hydrophobe Tasche in der Polo-like Kinase 1 (Plk1) zu entdecken. Ein neuartiger Ligandenbindungsmodus konnte vorhergesagt und für den Entwurf eines neuen Liganden mit hoher Affinität für Plk1 genutzt werden. Eine Röntgenstrukturanalyse bestätigt eine spezifische Bindung des Liganden in der vorgesehenen Tasche.

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