6Y7T

Engineered conjugation of lysine-specific molecular tweezers with ExoS derived peptidic inhibitor enhance affinity towards target protein 14-3-3 through ditopic binding

Summary for 6Y7T

• Entry DOI: 10.2210/pdb6y7t/pdb
• Descriptor: 14-3-3 protein sigma, Exoenzyme S, SODIUM ION, ... (6 entities in total)
• Functional Keywords: protein-protein interactions, supramolecular ligands, molecular tweezers, protein recognition, hybrid ligands, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 117195.25

Authors

Guillory, X.,Ottmann, C. (deposition date: 2020-03-02, release date: 2021-03-31, Last modification date: 2024-11-13)

Primary citation

Guillory, X.,Hadrovic, I.,de Vink, P.J.,Sowislok, A.,Brunsveld, L.,Schrader, T.,Ottmann, C.
Supramolecular Enhancement of a Natural 14-3-3 Protein Ligand.
J.Am.Chem.Soc., 143:13495-13500, 2021

PubMed Abstract: Rational design of protein-protein interaction (PPI) inhibitors is challenging. Connecting a general supramolecular protein binder with a specific peptidic ligand provides a novel conceptual approach. Thus, lysine-specific molecular tweezers were conjugated to a peptide-based 14-3-3 ligand and produced a strong PPI inhibitor with 100-fold elevated protein affinity. X-ray crystal structure elucidation of this supramolecular directed assembly provides unique molecular insight into the binding mode and fully aligns with Molecular Dynamics (MD) simulations. This new supramolecular chemical biology concept opens the path to novel chemical tools for studying PPIs.

PubMed: 34427424
DOI: 10.1021/jacs.1c07095

Experimental method

X-RAY DIFFRACTION (2.5 Å)