Agonists, but not antagonists, alter the conformation of the hormone-binding domain of androgen receptor.
Androgen receptors synthesized by translation in vitro form dimeric aporeceptor complexes with an androgen response element (ARE). Physiological and synthetic androgens elicit a conformational change in the receptor, which increases the mobility of receptor-ARE complexes in gel retardation assays. Neither a steroidal (cyproterone acetate) nor a non-steroidal (casodex) antiandrogen brings about the same effect and, at high concentrations, reverse the action of androgen agonists. When receptor-agonist complexes are subjected to a limited trypsin or chymotrypsin digestion, a protease-resistant 30-kDa fragment corresponding to the entire ligand-binding domain is formed. A similar fragment is not protected in the presence of antiandrogens. The C-terminal origin of the protected region was verified using mutated receptor forms: a mutant with a large N-terminal deletion behaves like the wild-type protein, but the properties of a hormone binding-negative receptor, due to a single-base substitution at codon 807, are not influenced by androgen agonists or antagonists.
Kallio
P J
PJ
Jänne
O A
OA
Palvimo
J J
JJ
D059002:Androgen Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D002474:Cell-Free System; D017373:Cyproterone Acetate / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases; D006801:Humans; D008715:Methionine / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification; D017354:Point Mutation; D014176:Protein Biosynthesis; D011487:Protein Conformation / Q000187:drug effects*; D051381:Rats; D011944:Receptors, Androgen / Q000737:chemistry* / Q000187:drug effects; D013739:Testosterone / Q000494:pharmacology*; D014158:Transcription, Genetic
D059002:Androgen Receptor Antagonists; D010446:Peptide Fragments; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D017373:Cyproterone Acetate; D008715:Methionine; D010450:Endopeptidases