The Molecular Tweezer CLR01 Stabilizes a Disordered Protein–Protein Interface

• DOI: 10.1021/jacs.7b07939
• Publication Date: 2017-10-17T17:51:26Z
• Authors: David Bier; Sumit Mittal; Kenny Bravo-Rodri...; Andrea Sowislok; Xavier Guillory; Jeroen Briels; Christian Heid; Maria Bartel; Burkhard Wettig; Luc Brunsveld; Elsa Sanchez-Garcia; Thomas Schrader; Christian Ottmann
• Keywords: Molecular Recognition; Intrinsically Disordered Proteins; Protein ligand

Protein regions that are involved in protein-protein interactions (PPIs) very often display a high degree of intrinsic disorder, which is reduced during the recognition process. A prime example binding rigid 14-3-3 adapter proteins to their numerous partner proteins, whose motifs undergo an extensive disorder-to-order transition. In this context, it highly desirable control entropy-costly process using tailored stabilizing agents. This study reveals how molecular tweezer CLR01 tunes 14-3-3/Cdc25CpS216 interaction. crystallography, biophysical affinity determination and biomolecular simulations unanimously deliver remarkable finding: supramolecular "Janus" ligand can bind simultaneously flexible peptidic PPI motif well-structured protein. fills gap interface, "freezes" one conformational states intrinsically disordered Cdc25C protein enhances apparent first structural functional proof targeting interface