The sequence-structure-function relationship of intrinsic ERα disorder

The oestrogen receptor (ER or ERα), a nuclear hormone receptor that drives most breast cancer¹, is commonly activated by phosphorylation at serine 118 within its intrinsically disordered N-terminal transactivation domain^2,3. Although this modification enables oestrogen-independent ER function, its mechanism has remained unclear despite ongoing clinical trials of kinase inhibitors targeting this region^4-6. By integration of small-angle X-ray scattering and nuclear magnetic resonance spectroscopy with functional studies, we show that serine 118 phosphorylation triggers an unexpected expansion of the disordered domain and disrupts specific hydrophobic clustering between two aromatic-rich regions. Mutations mimicking this disruption rescue ER transcriptional activity, target-gene expression and cell growth impaired by a phosphorylation-deficient S118A mutation. These findings, driven by hydrophobic interactions, extend beyond electrostatic models and provide mechanistic insights into intrinsically disordered proteins⁷, with implications for other nuclear receptors⁸. This fundamental sequence-structure-function relationship advances our understanding of intrinsic ER disorder, crucial for developing targeted breast cancer therapeutics.