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Mutation of Histidine 874 in the Androgen Receptor Ligand-Binding Domain Leads to Promiscuous Ligand Activation and Altered p160 Coactivator Interactions

School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, Scotland, United Kingdom AB25 2ZD

Address all correspondence and requests for reprints to: Dr. Iain J. McEwan, School of Medical Sciences, Institute of Medical Sciences Building, University of Aberdeen, Foresterhill, Aberdeen, Scotland, United Kingdom AB25 2ZD. E-mail: iain.mcewan{at}abdn.ac.uk.

The androgen receptor (AR) signaling pathway is a major therapeutic target in the treatment of prostate cancer. The AR functions as a ligand-activated transcription factor in the presence of the cognate hormone ligands testosterone and dihydrotestosterone (DHT). We have characterized a highly conserved sequence at the C-terminal end of helix 10/11 in the ligand-binding domain (LBD), which is prone to receptor point mutations in prostate cancer. This sequence includes threonine 877 that is involved in hydrogen bonding to the D ring of the steroid molecule and leads to promiscuous ligand activation of the AR when mutated to alanine or serine. A second mutation in this region, H874Y, also results in a receptor protein that has broadened ligand-binding specificity, but retains an affinity for DHT (K_d = 0.77 nM) similar to that of the wild-type receptor. The structure of the mutant LBD, expressed in Escherichia coli, is not dramatically altered compared with the wild-type AR-LBD in the presence of DHT, but shows a modestly increased sensitivity to protease digestion in the absence of hormone. This mutant AR showed wild-type AR-LBD/N-terminal domain interactions, but significantly enhanced binding and transactivation activity with all three members of the p160 family of coactivator proteins. Together, these phenotypic changes are likely to confer a selective advantage for tumor cells in a low androgen environment resulting from hormone therapy.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   SRC-1  |  GRIP1  |  AIB1

Ligands:   17β-Estradiol  |  Dihydrotestosterone  |  Progesterone  |  Bicalutamide

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