1. An Introduction to Medicinal Chemistry 3/e PROTEINS AS DRUG TARGETS:
Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 6
PROTEINS AS DRUG TARGETS:
RECEPTOR STRUCTURE & SIGNAL TRANSDUCTION
Part 3: Section 6.7

2. Contents
Part 3: Section 6.7
4. Tyrosine kinase linked receptors
4.1. Structure
4.2. Reaction catalysed by tyrosine kinase
4.3. Epidermal growth factor receptor (EGF- R)
(2 slides)
4.4. Insulin receptor (tetrameric complex)
4.5. Growth hormone receptor
4.6. Signalling pathways (5 slides)
[9 slides]

3. 4. Tyrosine kinase linked receptors
Bi-functional receptor / enzyme
Activated by hormones
Over-expression can result in cancer

4. 4. Tyrosine kinase linked receptors
4.1 Structure
Ligand binding region
Extracellular
N-terminal
chain N H 2 C O
Cell membrane
Hydrophilic
transmembrane
region (a-helix)
Catalytic binding region
(closed in resting state)
Intracellular
C-terminal
chain

5. 4. Tyrosine kinase linked receptors
4.2 Reaction catalysed by tyrosine kinase N C O
Protein OH
Tyrosine
residue
kinase
Mg++
ATP
ADP
Phosphorylated
tyrosine P

6. 4. Tyrosine kinase linked receptors
4.3 Epidermal growth factor receptor (EGF- R)
EGF
Inactive EGF-R
monomers
Cell
membrane
Ligand binding
and dimerisation OH HO
Phosphorylation
ATP
ADP OP PO
Induced fit
opens tyrosine kinase
active sites
Link
Binding site for EGF
EGF - protein hormone - bivalent ligand
Active site of tyrosine kinase
Link

7. Link

8. 4. Tyrosine kinase linked receptors
4.3 Epidermal growth factor receptor (EGF- R)
Active site on one half of dimer catalyses phosphorylation of Tyr residues on other half
Dimerisation of receptor is crucial
Phosphorylated regions act as binding sites for further proteins and enzymes
Results in activation of signalling proteins and enzymes
Message carried into cell

9. 4. Tyrosine kinase linked receptors
4.4 Insulin receptor (tetrameric complex)
Insulin
Cell
membrane OH HO OP
Phosphorylation
ATP
ADP PO
Kinase active site
opened by induced fit
Insulin binding site
Kinase active site

10. http://www. vivo. colostate
Link

11. 4. Tyrosine kinase linked receptors
4.5 Growth hormone receptor
Tetrameric complex constructed in presence of growth hormone GH
GH binding
&
dimerisation OH
Binding
of kinases HO OP PO
ATP
ADP
Activation and
phosphorylation
GH receptors
(no kinase activity) OH HO
kinases
Kinase active site
opened by induced fit
Growth hormone binding site
Kinase active site

12. 4. Tyrosine kinase linked receptors
4.6 Signalling pathways P
Ligand
signalling protein
Ligand

13. inherent or associated
4. Tyrosine kinase linked receptors
4.6 Signalling pathways
1-TM Receptors
Tyrosine kinase
inherent or associated
Guanylate cyclase
Signalling proteins
cGMP
PLCg
IP3
kinase
GAP
Grb2
Others
Ca++
PKC
IP3 DG
PIP3

14. 4. Tyrosine kinase linked receptors
4.6 Signalling pathways
Receptor
binding
site OH HO
GROWTH FACTOR RECEPTOR
Tyrosine kinase
active site
(inactive)

15. 4. Tyrosine kinase linked receptors
4.6 Signalling pathways
Growth
factor
1) Binding of
growth factor
2) Conformational
change OH HO
Dimerisation OH HO
Phosphorylation OP PO OH HO OH
Binding and
phosphorylation
of Grb2
Grb2
Grb2 OP PO OP PO
GDP
GTP
Ras
Binding
Ras and
GTP/GDP
exchange

16. 4. Tyrosine kinase linked receptors
4.6 Signalling pathways OP PO
Ras
Gene transcription
Raf (inactive)
Raf (active)
Mek (inactive)
Mek (active)
Map kinase (inactive)
Map kinase (active)
Transcription
factor (inactive)
factor (active)

19. Assigned Reading:
An Introduction to Medicinal Chemistry by Graham Patrick, Chapter 6, pp

20. Homework Questions:
Briefly describe the three different families of membrane-bount receptors, including the relative speed of signal transduction.
Briefly describe the mechanism whereby a typical GPCR exerts its effect.