CHAPTER 3. Sequence Predictive Recognition of Proteins and Peptides by Synthetic and Natural Receptors

Cha, Erin; Clements, Nia; Hofman, Cristina; Lavoie, Brylee; Zile, Anna Van; Warden, Lois; Urbach, Adam R.

doi:10.1039/9781788019798-00062

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“…10,11 The selective binding of Q7 at N-terminal phenylalanine translates to selective binding in complex mixtures of the proteins human insulin and human growth hormone, which each have an Nterminal Phe. 12,15,18 The larger cavity size of Q8 can accommodate two guests simultaneously. The reversible, noncovalent dimerization by Q8 of two FGG peptides (G is Gly) translates effectively to the noncovalent dimerization of proteins tagged with this sequence.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Recognition is mediated by inclusion of the aromatic side chain within the Q n cavity and via ion-dipole interactions between the N -terminal ammonium group and CO groups on the Q n . The smaller cavity size of Q7 can accommodate the side chain of a single aromatic residue. , The selective binding of Q7 at N -terminal phenylalanine translates to selective binding in complex mixtures of the proteins human insulin and human growth hormone, which each have an N -terminal Phe. ,, The larger cavity size of Q8 can accommodate two guests simultaneously. The reversible, noncovalent dimerization by Q8 of two FGG peptides (G is Gly) translates effectively to the noncovalent dimerization of proteins tagged with this sequence. − The ability of Q8 to bind two different but complementary guests, such as 2,6-dihydroxynaphthalene and methyl viologen, has been applied to the noncovalent coupling of N -terminal tryptophan with methyl viologen or other electron-deficient guest, − as well as the coupling of N -terminal aromatic residues with N -terminal pentafluorophenylalanine .…”

Section: Introductionmentioning

confidence: 99%

“…There have been numerous studies of the binding properties of polypeptides with Q n receptors. − Cucurbit[7]uril (Q7) and cucurbit[8]uril (Q8) recognize the amino acid residues Phe (F), Tyr (Y), and Trp (W) when located at the N -terminal position. Recognition is mediated by inclusion of the aromatic side chain within the Q n cavity and via ion-dipole interactions between the N -terminal ammonium group and CO groups on the Q n .…”

Section: Introductionmentioning

confidence: 99%

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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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