PROTEINS AS DRUG TARGETS:

RECEPTORS

Structure and function of receptors

Globular proteins acting as a cells letter boxes

Located mostly in the cell membrane

Receive messages from chemical messengers coming from other cells

Transmit a message into the cell leading to a cellular effect

Different receptors specific for different chemical messengers

Each cell has a range of receptors in the cell membrane making it responsive to
different chemical messengers

Structure and function of

receptors
Nerve
Signal

Receptor

Nerve

Messenger

Cell
Nucleus

Response
Cell

Structure and function of receptors

Nerve1

Blood
supply

Hormone

Nerve2

Neurotransmitters

Structure and
Mechanism function of receptors

Receptorscontainabindingsite(holloworcleftinthereceptorsurface)thatis
recognisedbythechemicalmessenger

Bindingofthemessengerinvolvesintermolecularbonds

Bindingresultsinaninducedfitofthereceptorprotein

Changeinreceptorshaperesultsinadominoeffect

DominoeffectisknownasSignalTransduction,leadingtoachemicalsignal
beingreceivedinsidethecell

Chemicalmessengerdoesnotenterthecell.Itdepartsthereceptorunchanged
andisnotpermanentlybound

The domino effect is a chain reaction that occurs when a small change causes
a similar change nearby, which then causes another similar change, and so on
in linear sequence.

Mechanism

Structure and
function of receptors

Inducedfit

Messenger

Messenger

Messenger
Cell
Membrane

Receptor

Receptor

Cell

Cell

Receptor
Cell
message
Message

The binding site

Ahydrophobicholloworcleftonthereceptorsurfaceequivalenttotheactivesiteof
anenzyme

Acceptsandbindsachemicalmessenger

Containsaminoacidswhichbindthemessenger

Noreactionorcatalysistakesplace

Bindingsite

Bindingsite

ENZYME

Messenger binding
Introduction

Messenger

Inducedfit

Bindingsiteisnearlythecorrectshapeforthemessenger

Bindingalterstheshapeofthereceptor(inducedfit)

Alteredreceptorshapeleadstofurthereffectssignaltransduction

Messenger binding
Bondingforces

Ionic
Hbonding
vanderWaals

Example:

vdw
interaction

Hbond

Bindingsite

Ser

ionic
bond

H
CO2

Asp

Receptor

Phe

Substrate binding
Bondingforces

InducedfitBindingsitealtersshapetomaximise
intermolecularbonding
Phe

Phe

Ser

CO2

Asp

Intermolecularbondsnot
optimumlengthfor
maximumbindingstrength

Induced
Fit

Ser

H
CO2

Asp

Intermolecularbond
lengthsoptimised

Overall process of receptor/messenger interaction

M

M
M
RE

RE

R
Signaltransduction

Bindinginteractionsmustbe:
strongenoughtoholdthemessengersufficientlylongforsignal

transductiontotakeplace
weakenoughtoallowthemessengertodepart
Impliesafinebalance
Drugdesigndesigningmoleculeswithstrongerbinding
interactionsresultsindrugsthatblockthebindingsite

Signal transduction
Controlofionchannels

Receptorproteinispartofanionchannelproteincomplex

Receptorbindsamessengerleadingtoaninducedfit

Ionchannelisopenedorclosed

Ionchannelsarespecificforspecificions(Na+,Ca2+,Cl,K+)

Ionsflowacrosscellmembranedownconcentrationgradient

Activatesordeactivatesenzymecatalysedreactionswithincell

Signal transduction
Controlofionchannels

Hydrophilic
tunnel

Cell

membrane

Signal transduction
Controlofionchannels

Receptor

Binding
site

Cell
membrane

Fiveglycoproteinsubunits
traversingcellmembrane

Messenger

Induced
fit
Gating
(ionchannel
opens)

CationicionchannelsforK+,Na+,Ca2+(e.g.Nicotinic acetylcholine)
AnionicionchannelsforCl(e.g.GABAA)

Cell
membrane

Signal transduction
Controlofionchannels:

MESSENGER

ION
CHANNEL
(closed)

Cell
membrane
Cell

Ion
channel

RECEPTOR
BINDING
SITE

Lock
Gate

Ion
channel

ION
CHANNEL
(open)
Inducedfit
andopening
ofionchannel

Cell
membrane

Cell
membrane
Cell

Ion
channel

MESSENGER

Ion
channel

Cell
membrane

GABAA
Receptor

The GABA receptors are a class of

receptors that respond to the
neurotransmitter gamma aminobutyric
acid.

P2X4 Receptor Ion

Channel