Oligomerization enables the selective targeting of an intrinsically disordered region by a small molecule

This repository contains the source data, analysis outputs, and metadata for “Oligomerization enables the selective targeting of an intrinsically disordered region by a small molecule.” Datasets span NMR (CSPs, PREs), dynamic light scattering, microscale thermophoresis, turbidity/c_sat, HPLC-based small-molecule partitioning, fluorescence/DIC microscopy, FRAP, and a cell-based LacI tethering assay. Raw instrument exports, processed tables (CSV/XLSX), images (TIFF/JPEG/LSM/CZI), and analysis scripts (Python/R) are provided with per-folder READMEs. Files are organized by figure/panel. Protein backbone NMR assignments are deposited in BMRB; accession numbers are listed in the repository README. No personally identifiable or sensitive data are included.

Intrinsically disordered regions (IDRs) are challenging drug targets because they lack stable interaction sites for drug-like molecules. We studied the first small molecule targeting an IDR to be evaluated in a clinical trial and found that it interacts selectively with an oligomeric form of the protein, more structured than the monomeric state, that is stabilized by interactions involving aromatic residues in regions with helical propensity. We also found that this compound alters the network of interactions defining the conformational ensemble of its target, thus affecting its condensation properties, linked to its function as a transcription factor. These findings provide a framework for developing strategies to target intrinsically disordered regions with small molecules.