nuclear receptors2

Question 2

Type 1

Answer 2

Ligand binds in cytosol Dissociation of HSP–> homodimerization–> translocation –> nucleus Bind specific DNA sequences: HREs 2 half sets separated by variable length DNA 2nd half site: inverted sequence Receptors for cholesterol derived hormones: androgen receptor, glucocorticoid receptor, oestrogen receptor, progesterone receptor DOMAINS A-B: N terminal regulatory domain. AF1 usu very weak but synergises with AF 2 from E domain Highly variable sequence C: DNA binding domain. Highly conserved. 2 zinc fingers D: hinge region flexible connects DBD with LBD. E: ligand binding domain. Moderately conserved in sequence. Highly conserved in structure Alpha helical sandwich fold: filling: 3 antiparallel alpha helices flanked by 2 alpha on one side and 1 alpha helix on the other Binds co activator and co repressor proteins F: C terminal. Highly variable Depends on ligand binding

Question 3

Type 2

Answer 3

Retained in nucleus, regardless of ligand bindingbind as heterodimers usu with RXR to DNAThyroid hormone receptor, Vit D3 receptor, retinoic acid receptorno ligand–> complex with co-repressor proteinligand–> dissociation of co-repressor and recruitment of co-activatorRNA polymerase recruited to NR/DNA complexDNA–> mRNAbind to direct repeat

Question 4

Type 3

Answer 4

Orphan receptorsno known endogenous ligandFXR, LXR, PPAR bind fatty acids, bile acids/ sterols withlow affinitymay be metabolic sensorsCAR,PXR: xenobiotic sensors: upregulate CYP450 expression

Question 5

Type 4

Answer 5

bind as monomers/dimersonly single DBD of receptor to single half site