5M35

The molecular tweezer CLR01 stabilizes a disordered protein-protein interface

Replaces:  5JIT

Summary for 5M35

• Entry DOI: 10.2210/pdb5m35/pdb
• Related: 3UX0 5EWZ 5EXA
• Descriptor: 14-3-3 protein zeta/delta, M-phase inducer phosphatase 3, GLYCEROL, ... (6 entities in total)
• Functional Keywords: stabilization, 14-3-3, disordered ppi interface, cdc25c, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 54989.76

Authors

Bier, D.,Ottmann, C. (deposition date: 2016-10-14, release date: 2017-11-15, Last modification date: 2024-01-17)

Primary citation

Bier, D.,Mittal, S.,Bravo-Rodriguez, K.,Sowislok, A.,Guillory, X.,Briels, J.,Heid, C.,Bartel, M.,Wettig, B.,Brunsveld, L.,Sanchez-Garcia, E.,Schrader, T.,Ottmann, C.
The Molecular Tweezer CLR01 Stabilizes a Disordered Protein-Protein Interface.
J. Am. Chem. Soc., 139:16256-16263, 2017

PubMed Abstract: 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.

PubMed: 29039919
DOI: 10.1021/jacs.7b07939

Experimental method

X-RAY DIFFRACTION (2.38 Å)