Documenti di Didattica
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Compiled by:
Chikowe, I.
College of Medicine
Malawi
1
Receptors
Depression
Heart problems
Schizophrenia
Muscle fatigue and many more.
Too many messengers being released leading to overheating of target
cells (metaphorically)
Too few messengers being released making the cell sluggish
3
So drugs can either increase messengers or block messengers.
Nerve
Nerve
Signal
Messenger
Receptor
Response
Nucleus
Cell
Cell
Nerve 1
Nuclear receptor
10
11
Illustration of Mechanism
Induced fit
Messenger
Messenger
Messenger
Cell
Membrane
Receptor
Receptor
Cell
Cell
Receptor
Cell
message
Message
Binding site
Binding site
Binding site:
ENZYME
12
Receptor/Messenger Binding
M
M
M
RE
RE
Signal transduction
13
Example
vdw
interaction
H-bond
Binding site
Ser
ionic
bond
Phe
CO2
Asp
Receptor
14
Phe
Ser
CO2
Asp
Induced
Fit
Ser
H
CO2
Asp
Intermolecular bond
lengths optimised
15
Transmembrane signaling of
cell surface receptor
Summary of receptors
Ion Channels
18
Binding
site
Cell
membrane
Messenger
Induced
fit
Cell
membrane
Gating
(ion channel
opens)
MESSENGER
ION
CHANNEL
(closed)
Cell
membrane
Cell
Ion
channel
RECEPTOR
BINDING
SITE
Lock
Gate
Ion
channel
ION
CHANNEL
(open)
Induced fit
and opening
of ion channel
Cell
membrane
Cell
membrane
Ion
channel
MESSENGER
Ion
channel
Cell
membrane
Cell
20
Responsible for
neurotransmission
cardiac conduction
muscle contraction etc...
22
G-Protein-coupled Receptors
Second messengers
cAMP
cGMP
Ca
DAG
IP3
25
closed
open
G-protein
split
Here, receptor binds messenger leading to induced fit; opens a binding site
for signal protein (G-protein) and the G-Protein is destabilised then split.
26
G-Protein-Enzyme-linked receptors
EGF
PDGF
ANP
Insulin
27
Enzyme
active site
(closed)
active site
(open)
Intracellular
reaction
28
closed
active site
open
intracellular reaction
closed
29
Kinase-linked Receptors
31
Intracellular Receptors
DNA
RNA
proteins
32
Illustration
33
Regulation of Receptors
covalent modification,
Receptor upregulation
36
37
M
M
RE
RE
Signal transduction
Design of agonists
Agonist
Agonist
Induced fit
RE
RE
Signal transduction
39
H-bond
binding region
O
H
O2C
OH
NH2Me
Neurotransmitter
Binding site
Receptor
O
NH2Me
O C
2
Receptor
O
NH2M e
Binding site
O C
2
INDUCED
FIT
Binding site
Receptor
Design of Agonist
Ionic
binding
group
H-bonding
group
HO
van der Waals
-bonding
group
NH2Me
H
H2N
NH2Me
HO
NHMe
HO
H
H
H
Me
Hypothetical
neurotransmitter
NH2Me
CH2Me
NH2Me
II
O
O
CH2Me
Binding site
Receptor
NH2Me
Binding site
Receptor
No interaction
OH
OH
O
N H 2M e
H
NH M e
2
O 2C
H
Binding site
2 Interactions only
Mirror
H
O
H
H
O
H
O
Binding site
3 interactions
M eH2N
NH2Me
Enantiomers of
a chiral
molecule
O
NH2M e
NH2Me
OH
Binding site
2 interactions
45
H
Steric block
O
H
N
H2
CH 3
No Fit
H
O
Me
Me
Steric block
O2 C
Binding site
Agonist must have correct size and shape to fit binding site
Groups preventing access are called steric shields or steric
46
blocks.
Design of Antagonists
Me
H
O C
2
Binding site
OH
O C
2
48
Extra hydrophobic
binding region
HO
H-bond
binding region
HO
H
NH2Me
Hypothetical
neurotransmitter
Ionic binding
region
O
Asp
49
Hydrophobic
region
HO
HO
HO
Induced fit
HO
H
NH2Me
H
NH2Me
Asp
O
Asp
50
Hydrophobic
region
Hydrophobic
region
HO
HO
HO
HO
HO
H
NHMe
NHMe
Asp
O
Asp
Initial binding
51
Competitive (Reversible)
Antagonists
M
An
An
RE
52
Irreversible Antagonists
Covalent Bond
X
OH
OH
Irreversible antagonism
53
O
O
HO
Cl
Cl
Cl
Cl
Propylbenzilylcholine mustard
Irreversible
binding
Cl Nu
Nu
Nu
Nu
Antagonist
binding site
Receptor
Agonist
binding site
Cl
Receptor
Binding site
ACTIVE SITE
(open)
Receptor
ENZYME
Allosteric
binding site
Induced
fit
(open)
Receptor
ENZYME
Antagonist
messenger
Binding site
for antagonist
Binding site
for messenger
Receptor
Antagonist
Receptor
56
Partial Agonist
H
O
1
H
NHM e
O 2C
Receptor
Slight shift
NHM e
O 2C
2
Partial opening
of an ion channel
O
H
Receptor
Possible explanations
Agent binds but does not produce ideal induced fit for maximum effect
Agent binds to binding site in two different modes, one where the agent
acts as an agonist and one where it acts as an antagonist
Agent binds as an agonist to one receptor subtype but as an antagonist
57
to another receptor subtype.
Inverse Agonists
Inactive conformations
B) Addition of agonist
C) Addition of antagonist
Active conformation
Desensitization
1
O2C
Ion channel
O2C (closed)
O
Agonist
Receptor
NH3
O
Agonist
O2C
NH3
Agonist
NH3
P
Receptor
Receptor
Sensitization
Sensitization
Neurotransmitter
Normal response
Antagonist
No response
Receptor
synthesis
No response
Receptor
synthesis
Sensitization
Response
Increase
antagonist
Excess response
Dependence
No response
Stop
antagonist
Tolerance
No response
H
O
H2O
Hydrophic skeleton
Arg394
Oestradiol
H12
Coactivator
Coactivator
Oestradiol
DNA
Oestrogen
receptor
Dimerisation &
exposure of
AF-2 regions
Nuclear
transcription
factor
Transcription
Side
chain
His 524
Glu353
O
OH
H
O
Arg394
Raloxifene
Tamoxifen as an antagonist
for the estrogen receptor
O
Me2N
CH2CH3
Anticancer agent