Mechanism of antiandrogen action: conformational changes of the receptor

Mol Cell Endocrinol. 1994 Jun;102(1-2):R1-5. doi: 10.1016/0303-7207(94)90112-0.

Abstract

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.

MeSH terms

  • Androgen Antagonists / metabolism*
  • Androgen Antagonists / pharmacology
  • Animals
  • Dihydrotestosterone / pharmacology
  • Humans
  • Metribolone / pharmacology
  • Mice
  • Protein Conformation / drug effects
  • RNA, Messenger / analysis
  • Rabbits
  • Receptors, Androgen / chemistry*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Reticulocytes / metabolism
  • Trypsin / metabolism

Substances

  • Androgen Antagonists
  • RNA, Messenger
  • Receptors, Androgen
  • Dihydrotestosterone
  • Metribolone
  • Trypsin