title: On the role of flexibility in protein-ligand interactions: the example of p53 tetramerization domain.
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.
authors.affiliation: Institute for Research in Biomedicine, Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Gordo
authors.forename: Vera
authors.initials: V
authors.lastname: Martos
authors.forename: Marta
authors.initials: M
authors.lastname: Vilaseca
authors.forename: Margarita
authors.initials: M
authors.lastname: Menéndez
authors.forename: Javier
authors.initials: J
authors.lastname: de Mendoza
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
mesh_terms: D047250:Calixarenes / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D009154:Mutation; D010636:Phenols / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D010636:Phenols; D016159:Tumor Suppressor Protein p53; C121325:calix(4)arene; D047250:Calixarenes