Download 4. Tyrosine kinase linked receptors

Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 6
PROTEINS AS DRUG
TARGETS:
RECEPTOR STRUCTURE &
SIGNAL TRANSDUCTION
Part 3: Section 6.7
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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]
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4. Tyrosine kinase linked receptors
• Bi-functional receptor / enzyme
• Activated by hormones
• Over-expression can result in
cancer
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4. Tyrosine kinase linked receptors
4.1 Structure
Extracellular
N-terminal
chain
Ligand binding region
NH2
Hydrophilic
transmembrane
region (a-helix)
Cell membrane
Catalytic binding region
(closed in resting state)
Intracellular
C-terminal
chain
C O2 H
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4. Tyrosine kinase linked receptors
4.2 Reaction catalysed by tyrosine kinase
Tyrosine
kinase
Mg++
O
Protein
N
C
Protein
OH
Tyrosine
residue
ATP
ADP
O
Protein
N
C
Protein
O
Phosphorylated
tyrosine
residue
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P
4. Tyrosine kinase linked receptors
4.3 Epidermal growth factor receptor (EGF- R)
EGF
Ligand binding
and dimerisation
Cell
membrane
Phosphorylation
OH
HO
OH
Inactive EGF-R
monomers
OH
OP
PO
ATP
ADP
OP
Induced fit
opens tyrosine kinase
active sites
Binding site for EGF
EGF - protein hormone - bivalent ligand
Active site of tyrosine kinase
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OP
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
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4. Tyrosine kinase linked receptors
4.4 Insulin receptor (tetrameric complex)
Insulin
Phosphorylation
Cell
membrane
HO
OH
OH
OH
ATP
ADP
PO
OP
OP
Kinase active site
opened by induced fit
Insulin binding site
Kinase active site
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OP
4. Tyrosine kinase linked receptors
4.5 Growth hormone receptor
Tetrameric complex constructed in presence of growth hormone
GH
GH binding
&
dimerisation
Binding
of kinases
GH receptors
(no kinase activity)
Activation and
phosphorylation
ATP
HO
kinases
OH
HO
OH
OH
OH
OH
OH
ADP
PO
OP
Kinase active site
opened by induced fit
Growth hormone binding site
Kinase active site
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OP
OP
4. Tyrosine kinase linked receptors
4.6 Signalling pathways
Ligand
P
P
P
P
P
P
Ligand
P
P
P
P
signalling protein
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4. Tyrosine kinase linked receptors
4.6 Signalling pathways
1-TM Receptors
Tyrosine kinase
inherent or associated
Guanylate cyclase
Signalling proteins
PLCg
IP3
DG
Ca++ PKC
IP3
kinase
GAP
cGMP
Grb2
Others
PIP3
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4. Tyrosine kinase linked receptors
4.6 Signalling pathways
Receptor
binding
site
GROWTH FACTOR RECEPTOR
Tyrosine kinase
active site
(inactive)
HO
OH
HO
OH
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4. Tyrosine kinase linked receptors
4.6 Signalling pathways
Growth
factor
1) Binding of
growth factor
Dimerisation
Phosphorylation
2) Conformational
change
HO
HO
HO
OH
OH
HO
OH
HO
HO
OH
OHHO
PO
OH
OH
PO
PO
OP
OPPO
Binding
Ras and
Grb2
Binding and
phosphorylation
of Grb2
HO
OH
OH
PO
PO
PO
OP
OPPO
Grb2
OP
OP
OP
GTP/GDP
exchange
OP
PO
PO
PO
OP
OPPO
GDP
GTP
Ras
OP
OP
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OP
OP
4. Tyrosine kinase linked receptors
4.6 Signalling pathways
Gene transcription
OP Ras
PO
PO
PO
OP
OPPO
OP
OP
Raf (inactive)
Raf (active)
Mek (inactive)
Mek (active)
Map kinase (inactive)
Map kinase (active)
Transcription
factor (inactive)
Transcription
factor (active)
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