Details

Autor(en) / Beteiligte

• Nadal, Marta
• Prekovic, Stefan
• Gallastegui, Nerea
• Helsen, Christine
• Abella, Montserrat
• Zielinska, Karolina
• Gay, Marina
• Vilaseca, Marta
• Taulès, Marta
• Houtsmuller, Adriaan B.
• van Royen, Martin E.
• Claessens, Frank
• Fuentes-Prior, Pablo
• Estébanez-Perpiñá, Eva

Titel

Structure of the homodimeric androgen receptor ligand-binding domain

Ist Teil von

• Nature communications, 2017-02, Vol.8 (1), p.14388-14388, Article 14388

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• The androgen receptor (AR) plays a crucial role in normal physiology, development and metabolism as well as in the aetiology and treatment of diverse pathologies such as androgen insensitivity syndromes (AIS), male infertility and prostate cancer (PCa). Here we show that dimerization of AR ligand-binding domain (LBD) is induced by receptor agonists but not by antagonists. The 2.15-Å crystal structure of homodimeric, agonist- and coactivator peptide-bound AR-LBD unveils a 1,000-Å 2 large dimerization surface, which harbours over 40 previously unexplained AIS- and PCa-associated point mutations. An AIS mutation in the self-association interface (P767A) disrupts dimer formation in vivo , and has a detrimental effect on the transactivating properties of full-length AR, despite retained hormone-binding capacity. The conservation of essential residues suggests that the unveiled dimerization mechanism might be shared by other nuclear receptors. Our work defines AR-LBD homodimerization as an essential step in the proper functioning of this important transcription factor. The androgen receptor is crucial for the development and physiology of reproductive organs. Here the authors present the structure of the androgen receptor ligand-binding domain bound to dihydrotestosterone, identifying a homodimerization interface that is crucial for receptor activity in vivo .