Androgen
From DrugPedia: A Wikipedia for Drug discovery
Androgen receptor Add an annotation
No Pfam abstract. Interpro entry IPR001103
Steroid or nuclear hormone receptors (NRs) constitute an important super-family of transcription regulators that are involved in diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members include the steroid hormone receptors and receptors for thyroid hormone, retinoids and 1,25-dihydroxy-vitamin D3. The proteins function as dimeric molecules in the nucleus to regulate the transcription of target genes in a ligand-responsive manner PUBMED:7899080, PUBMED:8165128.
NRs are extremely important in medical research, a large number of them being implicated in diseases such as cancer, diabetes and hormone resistance syndromes. Many do not yet have a defined ligand and are accordingly termed "orphan" receptors. More than 300 NRs have been described to date and a new system has recently been introduced in an attempt to rationalise the increasingly complex set of names used to describe superfamily members.
The androgen receptor (AR) consists of 3 functional and structural domains: an N-terminal (modulatory) domain; a DNA binding domain () that mediates specific binding to target DNA sequences (ligand-responsive elements); and a hormone binding domain. The N-terminal domain (NTD) is unique to the androgen receptors and spans approximately the first 530 residues; the highly-conserved DNA-binding domain is smaller (around 65 residues) and occupies the central portion of the protein; and the hormone ligand binding domain (LBD) lies at the receptor C-terminus. In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity.
The LBDs of steroid hormone receptors fold into 12 helices that form a ligand-binding pocket. When an agonist is bound, helix 12 folds over the pocket to enclose the ligand PUBMED:12089231. When an antagonist is unbound, helix 12 is positioned away from the pocket in a way that interferes with the binding of coactivators to a groove in the hormone-binding domain formed after ligand binding. In AR, ligand binding that induces folding of helix 12 to overlie the pocket discloses a groove that binds a region of the NTD. Coactivator molecules can also bind to this groove, but the predominant site for coactivator binding to AR is in the NTD. AR ligand resides in a pocket and primarily contacts helices 4, 5, and 10. The DNA-binding region includes eight cysteine residues that form two coordination complexes, each composed of four cysteines and a Zn2+ ion. These two zinc fingers form the structure that binds to the major groove of DNA. The second zinc finger stabilizes the binding complex by hydrophobic interactions with the first finger and contributes to specificity of receptor DNA binding. It is also necessary for receptor dimerization that occurs during DNA binding
Defects in the androgen receptor cause testicular feminisation syndrome, androgen insensibility syndrome (AIS) PUBMED:1307250, PUBMED:1569163. AIS may be complete (CAIS), where external genitalia are phenotypically female; partial (PAIS), where genitalia are substantively ambiguous; or mild (MAIS), where external genitalia are normal male, or nearly so. Defects in the receptor also cause X-linked spinal and bulbar muscular atrophy (also known as Kennedy's disease).
ANDROGENS
Androstenedione A4 or AD 4-androstene-3,17-dione 11beta-hydroxyandrostenedione betaA4 or betaAD 11beta-4-androstene-3,17-dione 5alphaAndrostanediol Adiol or 3alph5alphaAdiol 5alpha-androstane-3alpha,17beta-diol Androsterone AN 3alpha-hydroxy-5alpha-androstan-17-one Epiandrosterone epiAN 3beta-hydroxy-5alpha-androstan-17-one Andronosterone AT 4-androstene-3,11,17-trione Dehydroepiandrosterone DHEA or DHA 3beta-hydroxy-5-androsten-17-one Testosterone T 17beta-hydroxy-4-androsten-3-one Epitestosterone epiT 17alpha-hydroxy-4-androsten-3-one 5alpha-dihydrotestosterone DHT or 5alphaDHT 17beta-hydroxy-5alpha-androstan-3-one 5beta-dihydrotestosterone 5betaDHT 17beta-hydroxy-5beta-androstan-3-one 11beta-hydroxytestosterone OHT or betaT 11beta,17beta-dihydroxy-4-androsten-3-one 11-ketotestosterone KT 17beta-hydroxy-4-androsten-3,17-dione
Dehydroepiandrosterone (DHEA) is a natural steroid prohormone produced from cholesterol by the adrenal glands, the gonads, adipose tissue, brain and in the skin (by an autocrine mechanism). DHEA is the precursor of androstenedione, which can undergo further conversion to produce the androgen testosterone and the estrogens estrone and estradiol. DHEA is also a potent sigma-1 agonist.[76]
