The Molecular Tweezer CLR01 Stabilizes a Disordered Protein–Protein Interface
| Autor: | Christian Heid, Elsa Sanchez-Garcia, Christian Ottmann, Andrea Sowislok, David Bier, Jeroen Briels, Sumit Mittal, Kenny Bravo-Rodriguez, Burkhard Wettig, Thomas Schrader, Luc Brunsveld, Maria Bartel, Xavier Guillory |
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| Přispěvatelé: | Chemical Biology |
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Entropy Amino Acid Motifs Chemie Supramolecular chemistry Plasma protein binding Ligands Biochemistry Article Catalysis 03 medical and health sciences Colloid and Surface Chemistry Protein structure Hydrolase Journal Article cdc25 Phosphatases Binding site Binding Sites Protein Stability Ligand Chemistry Signal transducing adaptor protein General Chemistry Intrinsically Disordered Proteins Crystallography 030104 developmental biology 14-3-3 Proteins Biophysics Peptides Protein Binding Entropy (order and disorder) |
| Zdroj: | Journal of the American Chemical Society, 139(45), 16256-16263. American Chemical Society Journal of the American Chemical Society |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.7b07939 |
| Popis: | 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 is binding of the rigid 14-3-3 adapter proteins to their numerous partner proteins, whose recognition motifs undergo an extensive disorder-to-order transition. In this context, it is highly desirable to control this entropy-costly process using tailored stabilizing agents. This study reveals how the molecular tweezer CLR01 tunes the 14-3-3/Cdc25CpS216 protein-protein interaction. Protein crystallography, biophysical affinity determination and biomolecular simulations unanimously deliver a remarkable finding: a supramolecular "Janus" ligand can bind simultaneously to a flexible peptidic PPI recognition motif and to a well-structured adapter protein. This binding fills a gap in the protein-protein interface, "freezes" one of the conformational states of the intrinsically disordered Cdc25C protein partner and enhances the apparent affinity of the interaction. This is the first structural and functional proof of a supramolecular ligand targeting a PPI interface and stabilizing the binding of an intrinsically disordered recognition motif to a rigid partner protein. |
| Databáze: | OpenAIRE |
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