8th Feb - Nuclear Receptors

Question 1

When were steroids first utilised as a drug?

Answer 1

1950s

Question 2

When were steroid receptors identified?

Answer 2

1960s

Question 3

Why are nuclear receptors easy to study?

Answer 3

As they can be switched on by adding hormones

Question 4

What are the two types of nuclear receptor?

Answer 4

Steroid receptors - unliganded in cytoplasm and sequestered by HSP90

RAR, TR, VDR etc receptors - unliganded receptors in the nucleus, often sitting on the target gene acting as a repressor. The stimuli can be intracellular or extracellular.

Question 5

Which region of the nuclear receptor shows high homology?

Answer 5

DBD

Question 6

How were the functional domains of a nuclear receptor identified?

Answer 6

Through creating chimeric receptors by switiching the domains of two receptors: glucocorticoid and oestrogen. This showed which domain was the DBD and which was the LBD as the chimeric receptors either responded to oestrogen and activated the glucocorticoid receptors or vice versa

Question 7

Outline the common domain organisation of an NR

Answer 7

Transactivation domain 1
DBD
NLS
Transactivation domain 2

Question 8

Which two NRs have no DBD and why?

Answer 8

DAX and SHP, as they modulate the activity of other receptors

Question 9

Why does every NR have 9 conserved cysteine residues?

Answer 9

To co-ordinate the zinc in the zinc finger region

Question 10

Outline the hormone response element

Answer 10

Palindromic in nature with 3 bases between each half site

Question 11

Give an example of a homodimeric NR

Answer 11

Oestrogen receptor

Human PS2

Question 12

Give an example of a heterodimeric NR

Answer 12

TR

RAR

Question 13

Where did NRs first appear?

Answer 13

In metazoans

Question 14

How many NRs are encoded in the human genome?

Answer 14

48

Question 15

What is the classification of NRs

Answer 15

Class 1 - Steroid Receptors
Class 2 -Heterodimers with RXR
Class 3- Orphan and monomeric receptors

Question 16

Therapeutically why would PPAR be targeted?

Answer 16

To treat obesity in older men

Question 17

Give an example of a drug that binds PPARalpha and its effect

Answer 17

Clofibrate

Increases triglyceride metabolism

Question 18

Give an example of a drug that targets PPARdelta/beta and its effect

Answer 18

GW501516
Affects Muscle fibre type, observed mice are more energetic, by dramatically increasing the proportion of slow twitch muscles

Question 19

Give an example of a drug that targets PPAR gamma and its effect

Answer 19

Thiazolidinedione

Insulin sensitivity

Question 20

Give an example of an NR inverse agonist used therapeutically

Answer 20

Tamoxifen

Question 21

What percentage of prescribed drugs target NR?

Answer 21

10%

Question 22

What NR is targeted for inflammation?

Answer 22

Glucocorticoid receptor

Question 23

Describe the structure of the LBD

Answer 23

Ligand specificity is partly the size and shape of the pocket and a few very specific polar interactions

Question 24

How is ligand specificity determined by structure of the LBD?

Answer 24

By the size and shape of the pocket created by the helical sandwich

Question 25

Why is the majority of the LBD non-polar, apart forma few specific interactions?

Answer 25

The specific interactions determine ligand specificity

The rest remain non-polar to allow translocation across the membrane

Question 26

How does the NR read the DNA sequence?

Answer 26

One helix inserts directly into the major groove of the conserved hexamers present in DNA response elements

Question 27

Give an example of a common dimerisation partner of RXR

Answer 27

RAR
VDR
TR