{'fraction_non_alphanumeric': 0.04940587867417136, 'fraction_numerical': 0.03314571607254534, 'mean_word_length': 4.673758865248227, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Hot-spot mimicry of a cytokine receptor by a small molecule

Protein–protein complexes remain enticing, but extremely challenging, targets for small-molecule drug discovery. In a rare example described earlier, a high-affinity small molecule, SP4206 (Kd ≈ 70 nM), was found to block binding of the IL-2α receptor (IL-2Rα) to IL-2 (Kd ≈ 10 nM). Recently, the structure of the IL-2/IL-2Rα complex was solved [Rickert, M., Wang, X., Boulanger, M. J., Goriatcheva, N., Garcia, K. C. (2005) Science 308:1477–1480]. Using structural and functional analysis, we compare how SP4206 mimics the 83-fold larger IL-2Rα in binding IL-2. The binding free energy per contact atom (ligand efficiency) for SP4206 is about twice that of the receptor because of a smaller, but overlapping, contact epitope that insinuates into grooves and cavities not accessed by the receptor. Despite its independent design, the small molecule has a similar, but more localized, charge distribution compared with IL-2Rα. Mutational studies show that SP4206 targets virtually the same critical “hot-spot” residues on IL-2 that drive binding of IL-2Rα. Moreover, a mutation that enhances binding to the IL-2Rα near these hot spots also enhances binding to SP4206. Although the protein and small molecule do bind the same hot spot, they trap very different conformations of IL-2 because of its flexible nature. Our studies suggest that precise structural mimics of receptors are not required for high-affinity binding of small molecules, and they show that there are multiple solutions to tight binding at shared and adaptive hot spots.