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 1: Sections

2. Contents
Part 1: Sections
1. Receptor superfamilies
2. Ion channel receptors (Ligand gated ion channels)
2.1. General structure (3 slides)
2.2. Structure of protein subunits (4-TM receptor subunits)
2.3. Detailed structure of ion channel
2.4. Gating (2 slides)
[9 slides]

3. 1. Receptor superfamilies
RESPONSE
TIME
msecs
seconds
minutes
ION CHANNEL RECEPTORS
G-PROTEIN COUPLED RECEPTORS
KINASE LINKED RECEPTORS
INTRACELLULAR RECEPTORS
MEMBRANE
BOUND

4. 2. Ion channel receptors (Ligand gated ion channels)
2.1 General structure
Binding site
Receptor
Messenger
Cell
membrane
Cell
membrane
INDUCED
FIT
‘GATING’
(ion channel
opens)
Five glycoprotein subunits
traversing cell membrane
Cationic ion channels for K+, Na+, Ca2+ (e.g. nicotinic) = excitatory
Anionic ion channels for Cl- (e.g. GABAA) = inhibitory

5. 2. Ion channel receptors (Ligand gated ion channels)
Transverse view (nicotinic receptor)
Binding
sites a g d b
Ion channel
Cell
membrane a d b g
Two ligand binding sites
mainly on a-subunits
2xa, b, g, d subunits

6. 2. Ion channel receptors (Ligand gated ion channels)
Transverse view (glycine receptor)
Binding
sites a b
Ion channel
Cell
membrane a b
Three ligand binding sites
on a-subunits
3xa, 2x b subunits

7. 4 Transmembrane (TM) regions
2. Ion channel receptors (Ligand gated ion channels)
2.2 Structure of protein subunits (4-TM receptor subunits)
Neurotransmitter binding region H 2 N C O
TM1
TM2
TM4
TM3
Cell
membrane
Extracellular loop
Intracellular
loop
Variable loop
4 Transmembrane (TM) regions
(hydrophobic)

8. 2. Ion channel receptors (Ligand gated ion channels)
2.3 Detailed structure of ion channel
Protein
subunits
TM4
TM3
TM2
TM1
Transmembrane
regions
Note: TM2 of each protein subunit ‘lines’ the central pore

9. of each protein subunit
2. Ion channel receptors (Ligand gated ion channels)
2.4 Gating
Neurotransmitter
binds
Induced fit
at binding site
‘Domino effect’
Rotation of 2TM regions
of each protein subunit
Open
Ion flow
Transverse view
of TM2 subunits
TM2
Closed
Cell
membrane
Transverse view
of TM2 subunits
TM2

10. Link

11. Link

12. 2. Ion channel receptors (Ligand gated ion channels)
2.4 Gating
Fast response measured in msec
Ideal for transmission between nerves
Binding of messenger leads directly to ion flows across cell membrane
Ion flow = secondary effect (signal transduction)
Ion concentration within cell alters
Leads to variation in cell chemistry