Phospho-ERα: structure, function, and intervention

The intrinsically disordered AF1 domain at the N-terminal region of the ER represents an underexplored yet promising therapeutic target. Though small molecules directly inhibiting the disordered regions of related transcription factors like p53 and androgen receptor (AR) have been discovered, parallel efforts on the ER-AF1 have lagged without structural insights into this intrinsically disordered region. Elucidating its structure-function dynamics is therefore critical for achieving AF1 repression, especially for the functionally critical phosphorylation at Ser118 (pS118) occurring in the AF1 region. However, investigating the AF1 domain poses significant challenges as its lack of well-defined structure makes it challenging to conventional structural techniques. Our lab has made vital progress in illuminating the disorder-function relationship of the intrinsically disordered ER-AF1 region — a primary therapeutic target to overcome anti-estrogen resistance.