GCPRs

Question 1

True or False

If you had to guess the target of a certain drug, your best bet is to guess G_protein coupled receptors

30-40% of FDA approved drugs target GPCRs.

In 2018, 700 drugs = 35% of approved drugs target GPCRs

Answer 1

True

Question 2

________ GPCRs with no known ligands. Make drug development for a given receptor extremely difficult.

Answer 2

Orphan GPCRs

Question 3

True or False

GPCRs are important for homeostasis, important for both sensing and physiological changes.

There are 226 non-sensory (olfactory, taste, vision) GPCRs that are yet to be targeted with existing drugs

Answer 3

All True

Question 4

Why is the G protein also called serpentine receptors?

Also, where do the conformational changes occur, which is also linked to the G protein?

Where can a ligand-binding site be located?

Where are the phosphorylation sites?

Do GPCRS form pores?

Answer 4

They have 7 transmembrane segments

Occurs in the 5 and 6 transmembrane segments.

Can be located on the external N-terminus or in the transmembrane helices

beta-ARK

No, they don’t form pores

Question 5

Beta-Adrenegeric receptors responds to __________ mediated through three different beta-adregic receptors.

_________ is found in the heart and in kidneyes.

______ is found in smmoth muscle, liver, and skeletal muscle.

______- is found in fat cells.

Answer 5

epinephrine

B1

B2

B3

Question 6

True or False

TM5 and TM6 were crucial for undergoing conformational changes which were causing a problem of crystallization (method for discovering the structure of G Protein) so Brian Kobilka replaced the intracellular loop of the B2-adrenergic receptor with lysozyme stabilized two flexible helices, allowing crystallization of the fusion protein and determination of the structure of this medically important membrane receptor.

Answer 6

True

Question 7

True or False for the following GPCRs Structure Statement

___There are 508 structure of 90 different GPCrs published

____ Structure differ in species, nature of protein itself

___ Structure does not differ in structure with or without the ligand (or G protein)

Answer 7

True

True

False, Structure does differ in structure with or without the ligand/G protein.

Question 8

______________ represent a major focus of current drug design and development of theraputics for domapine-related patholoocial states.

(recall: Structures with bound agonist provide specific information of geometrics and bounds formed between receptors and agonist, allows for ration design of new beta-blockers.

Answer 8

Human D3 Dopamine Receptors

Question 9

Part 1

How did the D3 Receptors represent the major focus of current drug design and development of therapeutics for dopamine?

Hint: Look at the images

Answer 9

D3 receptors are predominately located in brain areas considered important for psychotic symptoms

The idea of developing a D3 receptor antagonist might be useful to provide therapeutics other than psychotic drugs.

The problem is the structural similarity of the D3 and D2 receptors subtypes make the development of D3 selective antagonist a challenging task

Most of the drug conc will primarily affect D2 receptors due to D2 having the higher Bmac and more expressed, no effect of an antagonist will affect D3.

if you lower the affinity for D2 then there is a window where the drug can bind to d3 receptors.

Question 10

Part 2 of D3 Dopamine Receptor

__________ was not a useful drug for therapeutic modulation of D3, but it helps determine how the drug binds and begins to come with ideas on how we can modify the drug to change the affinity towards D3 and not D2. Scientists look at ___________ bonds to modified the drug.

Answer 10

Eticlopride

Non-convalent

Question 11

Choose the best option

(Class A / Class B / Class C / Class F / Class D / Olfactory receptors)

rhodpsin-like, largest group of GPCRS

~300 members of non-olfactory receptors

~100 are orphans

Answer 11

Class A

Question 12

Choose the best option

(Class A / Class B / Class C / Class F / Class D / Olfactory receptors)

secretin receptor family

~55 total

~20 known and ~35 orphans

Answer 12

Class B

Question 13

Choose the best option

(Class A / Class B / Class C / Class F / Class D / Olfactory receptors)

mGluR/pheromone receptor family

25 total

18 known and ~7 orphans

Answer 13

Class C

Question 14

Choose the best option

(Class A / Class B / Class C / Class F / Class D / Olfactory receptors)

Frizzled, 12 total

Answer 14

Class F

Question 15

True or False

Class D and E are in mammals

Answer 15

False

They are not

Question 16

True or False

Olfactory receptors: within class A, 1000 genes in humans, although up to 600 many be pseudogenes

Answer 16

True

Question 17

True or False

We know a few about certain GPCRs.

GPCRs with less citation are less important

Answer 17

False, We know a lot about GPCRs

False, they are not less important it is just we don’t know what reagent they use to study them.

Question 18

Fill in the blanks

_________ trigger homeostatic regulation of the ion (in the answer) in the blood, receptor bind to the ion, when the ion concentration is high receptors are active and trigger the ion removal signals.

______________ is caused by GPCRs loss of function.

____________ is cuased by GPCRs gain of function mututions.

Answer 18

Ca2+ sensing

Familial hypocalciruic hypercalcemia

Familial hypocalcemia

Question 19

____________ diease cause by GPCRs loss of funtion, which results in less thyroid stimulation.

__________- a disease caused by GPCRs gain of function mutation, which results in more thyroid stimulator, to distinguish away from grave disease.

Answer 19

Congenital hypothyroidism

Familial nonautoimmune hyperthroidism

Question 20

True or False

Diseases caused by GPCR’s loss of function and gain of function are interpreting homeostasis.

Answer 20

True

Question 21

Looking at the evolutionary tree, how can we predict the possible function of orphan GPCRs?

Black = known Red= Orphan

Answer 21

If orphan GPCRs are grouped together with known GPCRs then we can predict the orphan function is similar to itself sibling known GPCRs.