Mechanism of antiandrogen action: conformational changes of the receptor.
Androgen receptor mRNA was translated in vitro, and androgen- and antiandrogen-bound receptor complexes were studied using limited proteolytic digestion by trypsin. Partial proteolysis of androgen-bound receptor protein resulted in a 29-kDa proteolysis-resisting fragment, whereas antiandrogen binding stabilised a 35-kDa fragment. Both fragments contain the entire ligand binding domain, and the 35-kDa fragment extended into the hinge region of the receptor. Several antiandrogens show agonistic properties for a mutated androgen receptor (LNCaP cell variant); trypsin digestion of antiandrogen-bound mutated receptor also resulted in a 29-kDa fragment. Our results point to an important difference between antiandrogens and antagonists of other steroid hormone receptors. Antiandrogens result in protection of both the hinge region and C-terminus of the androgen receptor agonist proteolytic attack, whereas other studies showed that antiestrogens and antiprogestagens expose the C-terminal end of the ligand binding domain of their respective receptors to protease. Differences in conformation of the hinge region distinguish androgen-bound from antiandrogen-bound receptor complexes, which represents an important feature of antiandrogen action.
Kuil
C W
CW
Department of Endocrinology & Reproduction, Erasmus University Rotterdam, Netherlands.
Mulder
E
E
D000726:Androgen Antagonists / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D013196:Dihydrotestosterone / Q000494:pharmacology; D006801:Humans; D015741:Metribolone / Q000494:pharmacology; D051379:Mice; D011487:Protein Conformation / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012156:Reticulocytes / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D000726:Androgen Antagonists; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D015741:Metribolone; D014357:Trypsin