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Pharmacology > Superfamily 3 > Flashcards

Superfamily 3 Flashcards

1
Q

What is the name for SF 3 receptors?

A

Enzyme linked receptors

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2
Q

What is the structure of an SF 3 receptor?

A

An amine group? (NH2)
Agonist binding site
Catalytic domain
COOG group?
N and C terminals are connected by one transmembrane alpha helix

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3
Q

What receptors are linked to tyrosine kinase?

A

Insulin receptor
Insulin-like growth factor receptor
Epidermal growth factor receptor
Cytokine receptors

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4
Q

What receptors are linked to guanylate cyclase?

A

Atrial natriuretic peptide (ANP) receptor
Guanylin receptor family
Photoreceptor dark cycle

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5
Q

What bonds holds the two alpha units in an insulin receptor?

A

A sulphur bond
1 holds the entire molecule together
2 hold the individual elements together

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6
Q

Give an interesting fact about tyrosine kinase

A

More than 90 tyrosine kinases have been identified but only 2/3 are receptor linked

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7
Q

What happens when an agonist binds to a tyrosine kinases linked receptor?

A

Altered conformation results in (augmented) receptor dimerisation

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8
Q

Is SF 3 are large family?

A

No it is relatively small and most of its receptors are linked to tyrosine kinase

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9
Q

What is different about the insulin receptor?

A

It is a loose dimer at rest

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10
Q

What are the steps of activation of tyrosine kinase receptors?

A

Rest
Conformational change (dimer formation)
Tyrosine autophosphorylation
Binding and phosphorylation of SH2 domain protein

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11
Q

When will SH2 proteins bind to the tyrosine kinase protein?

A

Only when the tyrosine molecules have been phosphorylated

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12
Q

What happens when the SH2 domain protein binds to the phosphorylated tyrosine?

A

The SH2 proteins become phosphorylated themselves and change shape - altering their own activity pathways

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13
Q

Explain how each tyrosine molecule becomes activated

A

If a tyrosine molecule is phosphorylated by a neighbouring dimer then there is potential for the 3 tyrosine molecules of each dimer to be activated
This can enhance activity by 200 fold if all three are activated

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14
Q

What about additional tyrosine sites within the receptors?

A

If these tyrosine sites are also activated they can then act as anchor points for the SH2 domains

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15
Q

How can tyrosine kinase receptors bind multiple SH2 domains at once?

A

Due to the multiple tyrosine sites

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16
Q

Explain the name SH2 domain

A

It appeared similar to the src oncogene production
Homologous to Src = SH2

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17
Q

How large is the SH2?

A

It is only 100 amino acids long, it is a smaller part of a larger protein

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18
Q

Why can SH2 be thought of as a jig saw piece?

A

The SH2 domain is meant to recognise phosphorylated elements of other proteins and bind/ attach to them
The way a jig saw piece would have to match another piece before connecting to it

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19
Q

If the SH2 domain cannot bind directly to Tyrosine kinase what must it use?

A

If the SH2 is binding indirectly then it will be done via docking proteins
These must also be phosphorylated before SH2 can bind to them

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20
Q

What is the purpose of the SH2 domain?

A

They can act as adaptors - meaning they can act as bridge connecting to the tyrosine kinase to other molecules
More often though they contain enzymes and transcription factors

21
Q

Give examples of proteins that contain a SH2 domain

A

RAS (small G protein) that activates mitogen activated protein kinases resulting in a signalling cascade
Phospholipase C gamma
Glucose transport proteins responsible for glucose uptake across cell membranes
Transcription factors that once activated by tyrosine kinase will translocate to the nucleus

22
Q

What is the thinking behind internalisation of activated receptor tyrosine kinases?

A

Initially thought to be involved in receptor desentisation, degradation and eventually recycling back to the cell surface
Now thought to also play a role in additional signalling to sub cellular targets such as nucleoplasm and mitochondria

23
Q

What are the thoughts behind activated tyrosine kinase works internally?

A

First assumed that the entire receptor protein would be trafficked in this way however it is more likely that only part of the receptor is trafficked this way

24
Q

What two things are responsible for moving part of the tyrosine kinase to work internally?

A

Secretases
Caspases

25
Q

What is the main distinction of the SF 3 receptors for cytokines?

A

They do not have a catalytic domain of tyrosine kinases
Instead they have a cytoplasmic kinase called JAK

26
Q

Do the cytokines receptors have any intrinsic kinase activity?

A

No
Since the receptor must closely associate with JAK it is referred to as a complex, this is what provides the receptor with the tyrosine kinase activity

27
Q

Give an example of an SH2 domain that specifically recognises JAK

A

STATs - a transcription factor that once bound to the activated JAK complex will travel to the nucleus and influence gene expression

28
Q

What is the termination mechanism for cytokine receptors?

A

To terminate the reaction, the phosphate groups that were added because of JAK must be removed

29
Q

What is responsible for dephosphorylating SF 3 tyrosine kinase receptors?

A

A family known as phosphoprotein tyrosine phosphatases will remove the phosphate groups and the receptor will return to its inactive state

30
Q

What other ways can the JAK/ STAT system be in deactivated?

A

Protein inhibitors (PIAS) which bind onto and inhibit activated STAT proteins
Suppressors of cytokine signalling (SOCS)

31
Q

Explain the SOCS pathway

A

SOCS expression is tightly regulated by STATs
Have a negative feedback control to block signalling
They possess SH2 domains which means they can bind onto the JAK protein and prevent STAT from binding
Able to promote the internalisation pathway to encourage degradation

32
Q

What cellular processes are regulated by tyrosine kinases linked receptors?

A

Metabolism (insulin)
Cell motility
Cell growth and differentiation
Cell division and transformation

33
Q

What area of drug development do tyrosine kinase receptors influence?

A

Cancer treatments
Metabolic
Inflammatory
Immunological disorders

34
Q

Give some examples of diseases associated with tyrosine kinase receptor mutations, chromosomal translocation, and gene amplification

A

Epidermal growth factor receptor - glioblastoma and excessive signalling (gene copy amplification)
Fibroblast growth factor receptor constitutively activated in lymphomas (chromosomal translocation)
Fibroblast growth factor receptor gain of function in bladder cancer (mutation)
Fibroblast growth factor receptor loss of function in developmental abnormalities (cleft palate) (mutations)

35
Q

What are the benefits to knowing which receptors are most affected by mutations etc?

A

They can be used as predictive bio markers to select potential responders to enrich clinical trial populations and get more accurate results

36
Q

Give two examples of small molecule inhibitors for tyrosine kinase activity

A

Sunitinib (renal cell carcinoma)
Gefitinib (displays some selectivity for epidermal growth factor receptor)

37
Q

How can drug resistance occur in tyrosine kinase receptors?

A

If a mutant version of tyrosine kinase receptors arises
Or there is recruitment of alternative signalling pathways

38
Q

Why are reserve therapies needed for the likes of growth factor signalling conditions?

A

There are multiple different pathways and even if the tyrosine kinase receptor is properly tested this may just lead to an up regulation of other pathways

39
Q

Which site do small molecule inhibitors target when treating tyrosine kinase receptors?

A

The ATP binding site in the catalytic domain
They are small and non selective between receptor and non receptor tyrosine sites

40
Q

Which other sites can novel tyrosine kinase inhibitors target?

A

They can specifically target the tyrosine kinase SH2 domain interactions (these would have to be simple molecules and act cytoplasmically)
Other small molecules that could bind to the ligand binding site and stop the agonist from binding and activating the receptor to begin with

41
Q

Why do the small molecule inhibitors target the ATP binding site?

A

This is because ATP is the primary source of phosphate within the cell that is used to phosphorylate other molecules

42
Q

Which two biological therapies target the extracellular domain of tyrosine kinase receptors?

A

Trastuzumab- hER2 receptor for breast cancer
Cetuximab - EGFR in colorectal cancer

43
Q

Name the biological therapy that complexes extracellularly with the ligand

A

Bevacizumab - VEGF inhibits tumour angiogenesis in bowel cancer
Targets the growth factor itself, and stops it from interacting with tyrosine kinase receptor all together

44
Q

What do biological therapies depend on?

A

Monoclonal antibodies
The antibodies recognise the domains as an antigen

45
Q

Are biological therapies enough on their own?

A

No their efficacy can be quite poor so they are combined with conventional chemotherapies for improved outcomes

46
Q

Can resistance develop for biological therapies?

A

Yes in a very similar way to drug resistance
Mutations
Recruitment of alternative pathways
Anti product antibodies

47
Q

Why should therapies be more target to specific receptors in specific areas of the body?

A

Tyrosine kinases influence many different signalling pathways, if they are all equally affected by the treatment there could be many more unwanted side effects

48
Q

Give a little detail on trastuzumab

A

It is not a cure for breast cancer
Instead it is a treatment to slow the growth and progression of the cancer
Elongating the patients life expectancy
Turning it into a chronic condition that can be managed

Pharmacology (18 decks)

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