A Binary Bivalent Supramolecular Assembly Platform Based on Cucurbit[8]uril and Dimeric Adapter Protein 14‐3‐3

• Published in: Angewandte Chemie International Edition Vol. 56; no. 31; pp. 8998 - 9002
• Main Authors: de Vink, Pim J., Briels, Jeroen M., Schrader, Thomas, Milroy, Lech‐Gustav, Brunsveld, Luc, Ottmann, Christian
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 24.07.2017; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: 14-3-3 protein; 14-3-3 Proteins - chemistry; 14-3-3 Proteins - metabolism; Adapter proteins; Adapters; Adaptor proteins; Amino Acid Motifs; Assembly; Binding Sites; Binding, Competitive; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - metabolism; Communication; Communications; cooperativity; Crystal structure; Crystallography, X-Ray; cucurbiturils; Dimerization; Epitopes; Epitopes - chemistry; Epitopes - metabolism; Estrogen receptors; Estrogens; Fluorescent Dyes - chemistry; Fluorometry; Glycine; host–guest systems; Imidazoles - chemistry; Imidazoles - metabolism; Molecular Dynamics Simulation; N-Terminus; Phenylalanine; Phosphopeptides - chemistry; Phosphopeptides - metabolism; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Proteins; Selective binding; supramolecular chemistry; adapter proteins; host-guest systems; cooperativity; cucurbiturils; supramolecular chemistry
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201701807

Interactions between proteins frequently involve recognition sequences based on multivalent binding events. Dimeric 14‐3‐3 adapter proteins are a prominent example and typically bind partner proteins in a phosphorylation‐dependent mono‐ or bivalent manner. Herein we describe the development of a cucurbit[8]uril (Q8)‐based supramolecular system, which in conjunction with the 14‐3‐3 protein dimer acts as a binary and bivalent protein assembly platform. We fused the phenylalanine–glycine–glycine (FGG) tripeptide motif to the N‐terminus of the 14‐3‐3‐binding epitope of the estrogen receptor α (ERα) for selective binding to Q8. Q8‐induced dimerization of the ERα epitope augmented its affinity towards 14‐3‐3 through a binary bivalent binding mode. The crystal structure of the Q8‐induced ternary complex revealed molecular insight into the multiple supramolecular interactions between the protein, the peptide, and Q8. Binary bivalent binding: The combination of a bivalent cucurbit[8]uril (Q8) host–guest complex with the bivalent protein 14‐3‐3 generated a binary assembly platform. Supramolecular induced switching between mono‐ and bivalent protein modes was observed and the elucidation of the first Q8‐protein cocrystal structure reported.