High Affinity Recognition of a Selected Amino Acid Epitope within a Protein by Cucurbit[8]uril Complexation

Sonzini, Silvia; Marcozzi, Alessio; Gübeli, Raphael J.; Walle, Christopher F. van der; Ravn, Peter; Herrmann, Andreas; Scherman, Oren A.

doi:10.1002/ange.201606763

Cited by 12 publications

(2 citation statements)

References 35 publications

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“…Prior work has shown a few examples of cucurbit [n]urils binding to nonterminal sites on peptides and proteins. 8,[12][13][14]16,17,49,50 Q7 binds to nonterminal F and Y with equilibrium dissociation constant (K d ) values in the millimolar to high-micromolar range. 11,12,51,52 By contrast, Q8-induced peptide dimerization at nonterminal sites occurs at low micromolar concentrations in certain contexts, 49 but not in others.…”

Section: ■ Introductionmentioning

confidence: 99%

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II β-Turn

Suating,

Kimberly,

Ewe

et al. 2024

J. Am. Chem. Soc.

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In an effort to target polypeptides at nonterminal sites, we screened the binding of the synthetic receptor cucurbit[8]uril (Q8) to a small library of tetrapeptides, each containing a nonterminal dipeptide binding site. The resulting leads were characterized in detail using a combination of isothermal titration calorimetry, 1 H NMR spectroscopy, electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS), and X-ray crystallography. The equilibrium dissociation constant values determined for the binding of Q8 to nonterminal dipeptide sites Lys-Phe (KF) and Phe-Lys (FK) were 60 and 86 nm, respectively. These are to the best of our knowledge the highest affinities reported to date for any synthetic receptor targeting a nonterminal site on an unmodified peptide. A 0.79 Å resolution crystal structure was obtained for the complex of Q8 with the peptide Gly-Gly-Leu-Tyr-Gly-Gly-Gly (GGLYGGG) and reveals structural details of the pair-inclusion motif. The molecular basis for recognition is established to be the inclusion of the side chains of Leu and Tyr residues, as well as an extensive network of hydrogen bonds between the peptide backbone, the carbonyl oxygens of Q8, and proximal water molecules. In addition, the crystal structure reveals that Q8 induces a type II β-turn. The sequence-selectivity, high affinity, reversibility, and detailed structural characterization of this system should facilitate the development of applications involving ligand-induced polypeptide folding.

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Section: ■ Introductionmentioning

confidence: 99%

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II β-Turn

Suating,

Kimberly,

Ewe

et al. 2024

J. Am. Chem. Soc.

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“…23 Scherman's group reported the first example of the recognition of a selected amino acid epitope within a protein by Q [8] complexation. 24 Isaacs's group obtained ''turn-on'' fluorescent sensors for amino acids using fluorescent cucurbituril derivatives. 25 In 2006 and 2016, our group reported supramolecular receptors for the detection and recognition of amino acids by TMeQ[6], 26 Q [7,8], 27 and twisted cucurbit [14]uril.…”

Section: ■ Introductionmentioning

confidence: 99%

Binding and Selectivity of Essential Amino Acid Guests to the Inverted Cucurbit[7]uril Host

et al. 2017

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Interactions between inverted cucurbit[7]uril (iQ[7]) and essential amino acids have been studied at pH = 7.0 by 1 H NMR spectroscopy, electronic absorption spectroscopy, isothermal titration calorimetry, and mass spectrometry. The interactions can be divided into three binding types at pH = 7.0. Experimental results from the present study showed that the host displays a strong binding to the aromatic amino acids, Trp and Phe, and the guests of Lys, Arg, and His lie outside the cavity portal of the host. Meanwhile, the alkyl moieties of the guests Met, Leu, and Ile were accommodated within the cavity of iQ[7], but there was no significant interaction between iQ[7] and Thr or Val. The complexation behavior of iQ[7] with essential amino acids was explored at pH = 3, and the binding of Lys, Arg, and His revealed an unexpected behavior, with their side chains located in the cavity of iQ[7], whereas those of the aromatic Trp and Phe were deeper within the iQ[7] cavity. The alkyl side chains of the guests Met, Leu, Ile, Thr, and Val were also located inside the iQ[7] cavity and formed the host–guest complexes.

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

et al. 2017

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Interactions between proteins frequently involve recognition sequences based on multivalent binding events. Dimeric 14-3-3 adapter proteins are aprominent example and typically bind partner proteins in aphosphorylation-dependent mono-or bivalent manner.H erein we describe the development of ac ucurbit [8]uril (Q8)-based supramolecular system, which in conjunction with the 14-3-3 protein dimer acts as abinary 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 a (ERa)f or selective binding to Q8. Q8-induced dimerization of the ERa epitope augmented its affinity towards 14-3-3 through ab inary bivalent binding mode.T he crystal structure of the Q8-induced ternary complex revealed molecular insight into the multiple supramolecular interactions between the protein, the peptide,a nd Q8.Supramolecular systems have shown great potential for the modulation of biomolecular assemblies. [1][2][3][4] Theselective and strong recognition of peptide and protein elements in particular by synthetic supramolecular host molecules has attracted significant attention. [5][6][7][8][9][10] These prior studies have laid the foundation for supramolecularly controlled protein dimerization, functioning, and assembly orthogonal to natural recognition and switching events. [3,[11][12][13] Notable examples include the dimerization of carbonic anhydrase by the use of as ynthetic foldamer platform [14,15] and the cucurbit[8]uril (Q8)-mediated functional reconstitution of as plit luciferase enzyme.[16] Thes tudy and modulation of protein-protein interactions (PPIs) is one of the most progressive areas of chemical biology and important for both fundamental research and drug discovery. [17,18] Protein assemblies frequently employ multivalent binding events,but the switching of this multivalency, for example between mono-and bivalent states,i sn ot readily modulated by classical small molecules. Thedistinctive structural and functional features of synthetic supramolecular systems are generating new modes for modulating such protein assemblies that act in an orthogonal manner to classical small-molecule modulation.[18] Within this context, the generation of multivalent supramolecular protein assemblies and their structural elucidation requires urgent attention.The1 4-3-3 adapter proteins are an especially interesting protein class because of their interaction with several hundred protein partners,m any of which are involved in human disease, [19,20] including the breast-cancer target, estrogen receptor a (ERa).[21] They are dimerized proteins that typically bind their partner proteins through short, phosphorylated motifs [22] either at two single-motif binding sites or at atandem binding site,which greatly enhances the binding affinity.[23] Whereas PPIs with the 14-3-3 monomer can be modulated by natural products, [23] peptide derivatives, [22,24,25] synthetic molecules, [26] or supramolecular ligands, [3] molecul...

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High Affinity Recognition of a Selected Amino Acid Epitope within a Protein by Cucurbit[8]uril Complexation

Cited by 12 publications

References 35 publications

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II β-Turn

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II β-Turn

Binding and Selectivity of Essential Amino Acid Guests to the Inverted Cucurbit[7]uril Host

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

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