Table 1.
Summary of NMR studies on supramolecular ligands binding to protein surfaces.
| Supramolecular ligand | Protein name, function | Main interaction site(s) | Ligand function | Ref. |
| molecular tweezer (CLR01) | p97 N-domain, cofactor binding domain of AAA ATPase |
6 patches with Lys & Arg: K20, K63/K60, K148/R113, R86/R144/R155, R159/K164, K190 | inhibition of protein–protein interaction with cofactor UBXD1 | [7] |
| molecular tweezer (CLR01) | hPin1-WW domain, substrate binding domain of peptidyl prolyl cis-trans isomerase | Lys & Arg, sterically accessible with basic residue in vicinity; preferred site R17, no binding to R36 | NMR methodology study | [80] |
| molecular tweezer (CLR01) | tau, microtubule-binding protein, amyloid-forming |
multiple Lys residues | inhibition of Tau fibril formation | [81] |
| molecular tweezer (CLR01) | ubiquitin, protein quality control |
Arg-rich C-terminus (most sterically accessible) & Lys 48 | binding model study | [82] |
| meso-tetrakis(4-sulfonatophenyl)- porphyrin (TPPS) |
ubiquitin, protein quality control |
hydrophobic triad (L8, I44, V70) and surrounding cationic residues | binding model study | [82] |
| pyrene tetrasulfonic acid (4PSA) | ubiquitin, protein quality control |
most (9 out of 12) cationic residues | binding model study | [82] |
| sulfonato-calix[4]arene (SCLX4) | ubiquitin, protein quality control |
Arg-rich C-terminus (most sterically accessible) | binding model study | [82] |
| sulfonato-calix[4]arene (SCLX4) | cytochrome c, electron carrier protein |
large Lys-containing patches around K87 & K4; at least 2 sites per protein | binding model study; protein camouflage | [20] |
| phosphonato-calix[6]arene (PCLX6) | cytochrome c, electron carrier protein |
N- and C-terminus with K4, K11, K100; at least 2 sites per protein | ligand-induced protein dimers in solution, ligand-induced protein assembly in crystal | [23] |
| sulfonato-calix[8]arene (SCLX8) | cytochrome c, electron carrier protein |
large Lys-containing patches around K4; K86/K87, K100; at least 2 sites per protein | ligand-induced protein tetramers in solution, dissociation of tetramers with excess (>2×) ligand; ligand-induced protein assembly in crystal | [24] |
| p-phosphonatomethyl-calix[4]arene (PMCLX4) | cytochrome c, electron carrier protein |
large Lys-containing patches, largest shifts around K86/K87, line broadening around K4, K11; at least 2 sites per protein | binding model study; ligand-induced protein assembly | [26] |
| sulfonato-calix[4]arene (SCLX4) |
Penicillium chrysogenum antifungal protein (PAF), antifungal protein |
K30 | binding model study; ligand-induced protein assembly | [25] |
| sulfonato-calix[6]arene (SCLX6) |
Penicillium chrysogenum antifungal protein (PAF), antifungal protein |
K30 and weaker binding to K6, K42; strong line broadening | binding model study; ligand-induced protein assembly | [25] |
| sulfonato-calix[8]arene (SCLX8) |
Penicillium chrysogenum antifungal protein (PAF), antifungal protein |
K30, strong line broadening | binding model study; ligand-induced protein assembly | [25] |
| bromo-sulfonato-calix[4]arene (Br.SCLX) | cytochrome c, electron carrier protein |
large Lys-containing patches, strongest shifts at K86; line broadening | binding model study | [27] |
| phenyl-sulfonato-calix[4]arene (Ph.SCLX) | cytochrome c, electron carrier protein |
large Lys-containing patches, strongest shifts around K4/K5 and K86; severe line broadening | binding model study | [27] |
| PEGylated sulfonato-calix[4]arenes (SCLX4-PEG1 and SCLX4-PEG2) | cytochrome c, electron carrier protein |
large Lys-containing patches, tight binding to K4, weaker binding to K86 | binding model study | [28] |
| sulfonato-calix[4]arenes with additional aromatic substituent | K9-trimethylated histone 3 peptide, chromosome organization | trimethyl-Lys (K9Me3) | inhibition of interaction with plant homeodomain (PHD) of chromodomain helicase DNA-binding protein 4 (CHD4) | [31] |
| sulfonato-calix[4]arenes with additional aromatic substituent | K4-trimethylated methylated histone 3 peptide, chromosome organization | trimethyl-Lys (K4Me3), trimethyl-Lys (K9Me3) | up to 10× selectivity towards H3K4Me3 over H3K9Me3, inhibition of interaction with ING2 plant homeodomain (PHD) | [32] |
| guanidiniomethyl-calix[4]arene with 2 hydrophobic loops at the narrow rim | tetramerization domain (TD) of p53, transcription factor, tumor suppressor |
hydrophobic clefts between two of the monomers each, at each side of the tetramer | recovering the tetramer integrity and stability of p53-R337H mutant protein | [40] |
| cucurbit[7]uril | R. solanacearum lectin, carbohydrate-binding protein | dimethylated lysine (KMe2), sterically accessible | KMe2 recognition, protein assembly | [50–51] |
| bivalent guanidinocarbonyl-pyrrole (GCP) ligand | survivin (residues 1-120), anti-apoptotic protein, part of chromosomal passenger complex |
Glu/Asp-rich histone H3 binding site | inhibition of protein–protein interaction with histone 3 | [46] |
| porphyrins with carboxylate substituents (Coproporphyrin I and 5,10,15,20-Tetrakis(3,5-dicarboxylato- phenyl)-porphyrin) |
cytochrome c, electron carrier protein |
dynamic ensemble including patches with varying hydrophobicity and positive electrostatic charge, overall 1:1 stoichiometry | binding model study | [59] |
| RuII(bpy)3 complexes with carboxylate substituents | cytochrome c, electron carrier protein |
Cyt c peroxidase binding site (ring-shaped positively charged patch) | inhibition of protein–protein interaction with Cyt c peroxidase | [63] |