Dendrimers as Competitors of Protein-Protein Interactions of the Intrinsically Disordered Nuclear Chromatin Protein NUPR1.
Neira JL, Correa J, Rizzuti B, Santofimia-Castaño P, Abian O, Velázquez-Campoy A, Fernandez-Megia E, Iovanna JL
NUPR1 is a protumoral multifunctional intrinsically disordered protein, which is activated during the acute phases of pancreatitis, interacting with several biomolecules through residues around Ala33 and Thr68. Because of the large size of this hot-spot, designed small molecules could be insufficient to modulate all NUPR1 functions. In this work, we studied NUPR1 interactions with dendrimers by using biophysical techniques and in silico methods. Our results, obtained with different functionalized dendrimers (anionic, cationic and neutral) and several of their generations, indicate that NUPR1 was bound to the dendrimers. Functionalities at the dendrimer periphery modulated the affinity for NUPR1, and for any dendrimer, the affinity increased with generation. The affinities of most of the dendrimers were in the range 4-40 × 10 M, and those of the [Gn]-PhCONa dendrimers were similar to those of NUPR1 for its natural partners (0.1-1 × 10 M). In all dendrimers, the residues of NUPR1 first affected upon binding were located around Ala33, indicating that NUPR1 employs the same hot-spot to recognize any natural or synthetic molecule.Lire l‘article