Theme 2 Lecture 5

Question 1

Types of Target and Ways of Targeting

Answer 1

GPCRS
RTKS
Protein-protein interactions

Question 2

GPCRS examples

Answer 2

Orphan receptors
Biased signalling, allosterism, heteromers
Virally encoded receptors

Question 3

RTKS examples

Answer 3

Antibodies- trastuzumab and herceptin
PKIs=Imatinib

Question 4

Protein-Protein Interactions examples

Answer 4

BRET and FRET
Rapamycin

Question 5

What is the GPCR role

Answer 5

They are G protein coupled receptors which detect molecules outside of the cells and make intracellular pathways.

Question 6

What is the orexin system

Answer 6

The orexin system plays a part in the wakefulness
The two GPCR receptors OX1 and 2 are inhibited which prevents insomnia
Orexin Antagonists: These are aimed at treating insomnia by blocking the orexin system when sleep is desired.
–Orexin Agonists: These are developed to mimic the effects of orexin and alleviate narcolepsy symptoms in the long term.

Question 7

Explain GPCR Allosterism and Bias

Answer 7

Allosteric- Changes FUNCTIONAL CHANGE on GPCR
Orthosteric- Molecule binding to the same site as the ligand
Biased signalling- preference of a receptor to allow certain signalling
Homo- dimerisation of same receptor (cooperative) HER1 and HER1
Heter- dimerisation of different receptor (biased) HER1 and HER2

Question 8

CaSR role and drug

Answer 8

CaSR maintains calcium homeostasis.
Cinacalcet is a calcimimetic that allosterically modulates CaSR.

Question 9

Virally encoded GPCRS

Answer 9

These GPCRS are highly druggable and show a high agonist response

Question 10

HER2 Pathways AND drugs

Answer 10

This family (EGFR=HER1,HER2 etc) plays a role in signalling pathways that lead to cell growth and differentiation.
Drugs include Trastuzumab (Herceptin),
Pertuzumab = PREVENTS dimerisation of HER3
Lapatinib TKI that binds to EGFR and HER2 (BREAST CANCER)

Question 11

Antibodies and Kinase inhibtors

Answer 11

Antibodies are in the extracellular domain which include the mabs.
Kinase inhibitors the the ibs and are in the intracellular domains

Picture the diagram in the lecture with the different signalling pathways and where the drugs act.

Question 12

HER Receptors, Activation of kinase domain

Answer 12

Agonist binding causes dimerisation
Receptor phosphorylationof the kinase domain causes intracellular signalling.

Question 13

What can BRET be used for to study the formation of?

Answer 13

BRET can be used to study the formation of VEGFR2 homodimers and ligand binding.

Question 14

How does FRET work?

Answer 14

Energy transfer from a donor fluorophore to an acceptor fluorophore
When in a close proximity light is emitted which overlaps with the acceptor fluorophore
So can be used to find distances of molecules

Question 15

Rapamycin

Answer 15

Used as an immunosuppressant in the kidney
Rapamycin binds to FKP12 inhibiting kinases of MTOR
Thus leading to decreased protein synthesis.