L12 - nuclear receptors .pdf

Pharm 2210 lect 12 Study online at https://quizlet.com/_dax9fq 1. nuclear recep- ligand-activated transcription factors tors -7 sub fams, 48 nuclear receptors Dimerisation, DNA binding motif + intracellular ligand...

Pharm 2210 lect 12 Study online at https://quizlet.com/_dax9fq 1. nuclear recep- ligand-activated transcription factors tors -7 sub fams, 48 nuclear receptors Dimerisation, DNA binding motif + intracellular ligand binding Act w DNA directly via recog of response elements 2. Intracellurly Where NRs bind ligands 3. Xenobiotic re- Pregnane X receptor (PXR) ceptor Constitutive androstane resceptor (CAR) 4. Yes Do nuclear receptors undergo dimerisation? 5. NR heterodimer RXR partner 6. 4 types of nu- Steriod NR clear receptors RXR heterodimer Dimeric orphan NR Monomeric orphan NR 7. Steroid NR Ligand: glucocorticoid, estrogen Dimer: homodimer Location: Cytoplasm (common) or nucleus Response element (RE): INVERTED repeat (IR) eg. AG- GTCAnnnTGACCT 8. RXR Ligand: fatty acids, retinoic acids, cholesterol Dimer: heterodimer Loctation: nucleus (mostly) or cytoplasm Response element: DIRECT repeat eg. AGGTCAnAGGT- CA 9. Structure of a nu- N term domain clear receptor DNA binding domain Hinge region Ligand binding domain 10. N-Terminal do- Least conserved main (A/B) -varies in length and AA seq Activation function 1: binds co-regulators in a ligand-inde- 1/6  Pharm 2210 lect 12 Study online at https://quizlet.com/_dax9fq pendant manner Post translational mods 11. AF1 Binds co-regulators in a ligand-INdependant manner 12. DBD (DNA bind- HIGHLY conserved - responsible for DNA recog and bind- ing domain, C) ing Two zinc fingers formed by cys rich loops -1st zinc finger - recog specific hormone response ele- ments (HREs) -2nd zinc finger - role in dimerisation 13. DBD (C) Where zinc fingers are found 14. Hinge region (D) Links DBD and LBD; ^ flexible Contains nuclear localisation signal (NLS) - role in nuclear translocation -NLS can overlap with DBD 15. hinge region Region that allows flexibility for conformational change after ligand binding's 16. ligand binding Highly conserved domain (LBD, Hydrophobic pocket formed by 2 a-helices E/F) -helix 12: important role in co-activator/repressor switch- ing Main role in receptor dimerisation Activation function 2 (AF2): binds co-regulators in lig- and-DEPENDANT manner Post-translational mods 17. Af2 Binds co-regulators in ligand-DEPENDANT manner 18. Helix 12 role Important activator/repressor switching Determines WHAT binds to the domain Changes postions depending on: LBD-agonist-co-repres- sor complex Or LBD-antagonist-co-activator complex 2/6  Pharm 2210 lect 12 Study online at https://quizlet.com/_dax9fq 19. HPA axis Release of glucocorticoids (cortisol) -ve feedback adverse drug reaction - chronic use of GCs > adrenal suppression 20. Glucocorticoids Maintain homeostasis, respond to stress Reg. Metab. And immune responses Anti-inflammatory Immunosuppressive Cushing's > too much cortisol Action mediated by glucocorticoid receptor 21. glucocorticoid N term domain (A/B) receptor -sites for post transl mods DBD (C) -2 zinc fingers Hinge region (D) -NLS1 overlaps w end of DBD and hinge -NLS2 overlaps w LBD LBD (E/F) 22. GRs Encoded by Alt splicing of exon 9 > GRa and GRb NR3C1 gene -GRa mediates action of glucocorticoids GRy contains arginine insertion in DBD Other splice varients 23. GR mediated sig- Unliganded monomeric GR resides in the cytoplasm and nalling forms a complex w HSP90 and other chaperone proteins Ligand binding >GR dissociates from complex >expose nuclear localisation signals > GR translocated to nucleus 24. GR Signalling, Role of kinases non genomic 25. GR signalling, Transactivation genomic increase gene transcription 3/6  Pharm 2210 lect 12 Study online at https://quizlet.com/_dax9fq Transrepression decrease gene transcription 26. Types of GR me- A) Direct diated regulation B) tethering of gene tran- C) Composite scription 27. GR- DIRECT GR dimer binds DIRECT to GRE (GGAACAnnnTGTTCT), ^ gene transcription GR binds to negative GRE (IR nGRE, CTCC(n)0-2GGAGA, decrease transcription 28. GR- TETHERING GR interacts w other transcription factors Pro inflammatory GR bind direct to DNA-Bound AP-1 or NF-kB Suppression of these genes = anti inflammatory proper- ties of glucocorticoids 29. GR - COMPOS- Interacts w other transcription factors ITE GRE-bound GR interacts w neighbouring AP-1 or NF-kB Suppression of these genes = anti inflammatory proper- ties of glucocorticoids 30. post-translation- Acetylation (A) -limitd action of glucocorticoids on NF-kB al mod of GRa signalling Phosphorylation -change transcriptional activity and inter- action w co regulators Ubiquitination - facilitates degradation of GRs SUMOylation -alter transcription activity through coregu- lators 31. Small Ubiquitin SUMOylation, what does SUMO stand for Related Modifier 32. What does ubiq- targets a protein for degradation by a proteasome uitination do? 4/6  Pharm 2210 lect 12 Study online at https://quizlet.com/_dax9fq 33. Class2 NR-RXR Non permissive RXR het dimer heterodimers Permissive RXR het dimer 34. Non permissive eg. Thyroid hormone receptor, D vit receptor RXR het dimer Het dimer is activated by ligands of partner NR while RXR is silenced 35. Dimer can only Non permissive RXR because: be activated by the ligand for the non RXR partner, RXR silenced 36. Permissive RXR eg. Peroxisome proliferator-activated receptor heterodimer Het dimer is activated by ligands of either NR, w synergis- tic effects when both NRs activated 37. Dimer can be ac- Permissive RXR dimer: tivated by ligand for either partner 38. Peroxisome PPARa -liver,heart + brown adipose tissue - fatty acid proliferator-acti- oxidation vated receptors PPARb/delta -ubiquitous expression - FA oxidation (PPARs) PPARy -white + brown adipose - apidogenesis, lipid metab, insulin sensitivity 39. PPARy DIRECT repeat in DBD PPAR/RXR het dimer Ligand dépendant activation Can be activated w out ligand in EXTREME circumstances 40. PPARy function Adipocyte differentiation and mature adipocyte function Lipid metabolism Glucose homeostasis GLUT4 ^ PI3K ^ CAP^ IRS-1/IRS2^ 5/6  Pharm 2210 lect 12 Study online at https://quizlet.com/_dax9fq FGF1+FGF21 ^ PPARy activity FGF1 blocks SUMOylation of PPARy 41. post-translation- Acetylation al modification Phosphorylation of PPARy Ubiquitination SUMOylation 6/6