biostudies-literatureJaiprashad RNIGMS NIH HHS1887https://www.ebi.ac.uk/biostudies/studies/S-EPMC9775153biostudies-literatureUnknown12(12)Intrinsically disordered proteins (IDPs) are important in both normal and disease states. Small molecules can be targeted to disordered regions, but we currently have only a limited understanding of the nature of small-molecule binding sites in IDPs. Here, we show that a minimal small-molecule binding sequence of eight contiguous residues derived from the Myc protein can be ported into a different disordered protein and recapitulate small-molecule binding activity in the new context. We also find that the residue immediately flanking the binding site can have opposing effects on small-molecule binding in the different disordered protein contexts. The results demonstrate that small-molecule binding sites can act modularly and are portable between disordered protein contexts but that residues outside of the minimal binding site can modulate binding affinity.BiomoleculesPortability of a Small-Molecule Binding Site between Disordered Proteins.PMC97751531R15GM120698De Silva SRFred Lucena LMMeyer EMetallo SJJaiprashad RfalsePortability of a Small-Molecule Binding Site between Disordered Proteins.Intrinsically disordered proteins (IDPs) are important in both normal and disease states. Small molecules can be targeted to disordered regions, but we currently have only a limited understanding of the nature of small-molecule binding sites in IDPs. Here, we show that a minimal small-molecule binding sequence of eight contiguous residues derived from the Myc protein can be ported into a different disordered protein and recapitulate small-molecule binding activity in the new context. We also find that the residue immediately flanking the binding site can have opposing effects on small-molecule binding in the different disordered protein contexts. The results demonstrate that small-molecule binding sites can act modularly and are portable between disordered protein contexts but that residues outside of the minimal binding site can modulate binding affinity.2022-01-01T00:00:00Z2022 Dec2025-04-21T23:19:43.597Z2025-04-05T19:05:11.946ZS-EPMC97751533655131510.3390/biom12121887