On the Role of Flexibility in Protein–Ligand Interactions: the Example of p53 Tetramerization Domain

Authors

  • Dr. Susana Gordo,

    1. Institute for Research in Biomedicine, Baldiri Reixac 10, 08028 Barcelona (Spain), Fax: (+34) 93-403-7126
    2. Current address: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute - Harvard Medical School, 450 Brookline Ave, Boston, MA 02284 (USA)
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  • Dr. Vera Martos,

    1. Institut Català d'Investigació Química, Av. Països Catalans 16, 43007 Tarragona (Spain), Fax: (+34) 977-920-926
    2. Department of Organic Chemistry, Universidad Autónoma de Madrid, 28049 Cantoblanco, Madrid (Spain)
    3. Current address: Department of Medicinal Chemistry, Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Str.10, 13125 Berlin (Germany)
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  • Dr. Marta Vilaseca,

    1. Institute for Research in Biomedicine, Baldiri Reixac 10, 08028 Barcelona (Spain), Fax: (+34) 93-403-7126
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  • Dr. Margarita Menéndez,

    1. CSIC - Instituto Química Física Rocasolano, Serrano 119, 28006 Madrid (Spain)
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  • Prof. Javier de Mendoza,

    Corresponding author
    1. Institut Català d'Investigació Química, Av. Països Catalans 16, 43007 Tarragona (Spain), Fax: (+34) 977-920-926
    2. Department of Organic Chemistry, Universidad Autónoma de Madrid, 28049 Cantoblanco, Madrid (Spain)
    • Javier de Mendoza, Institut Català d'Investigació Química, Av. Països Catalans 16, 43007 Tarragona (Spain), Fax: (+34) 977-920-926

      Ernest Giralt, Institute for Research in Biomedicine, Baldiri Reixac 10, 08028 Barcelona (Spain), Fax: (+34) 93-403-7126

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  • Prof. Ernest Giralt

    Corresponding author
    1. Institute for Research in Biomedicine, Baldiri Reixac 10, 08028 Barcelona (Spain), Fax: (+34) 93-403-7126
    2. Department of Organic Chemistry, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona (Spain)
    • Javier de Mendoza, Institut Català d'Investigació Química, Av. Països Catalans 16, 43007 Tarragona (Spain), Fax: (+34) 977-920-926

      Ernest Giralt, Institute for Research in Biomedicine, Baldiri Reixac 10, 08028 Barcelona (Spain), Fax: (+34) 93-403-7126

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Abstract

The recognition of protein surfaces by designed ligands has become an attractive approach in drug discovery. However, the variable nature and irregular behavior of protein surfaces defy this new area of research. The easy to understand “lock-and-key” model is far from being the ideal paradigm in biomolecular interactions and, hence, any new finding on how proteins and ligands behave in recognition events paves a step of the way. Herein, we illustrate a clear example on how an increase in flexibility of both protein and ligand can result in an increase in the stability of the macromolecular complex. The biophysical study of the interaction between a designed flexible tetraguanidinium-calix[4]arene and the tetramerization domain of protein p53 (p53TD) and its natural mutant p53TD-R337H shows how the floppy mutant domain interacts more tightly with the ligand than the well-packed wild-type protein. Moreover, the flexible calixarene ligand interacts with higher affinity to both wild-type and mutated protein domains than a conformationally rigid calixarene analog previously reported. These findings underscore the crucial role of flexibility in molecular recognition processes, for both small ligands and large biomolecular surfaces.

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