MEDICINAL CHEMISTRY

Chapter 3

Receptor: Structures and Functions-

Signal Transduction
Instructor: Dr. Nguyen Thao Trang
Outlines
• Receptor structures and functions:
– Ion channels;
– G protein coupled;
– Kinase linked; and
– Intracellular

• Signal transduction
Receptors: Introduction
• Receptors are specific areas of certain proteins and
glycoproteins found either embedded in cellular membranes
or in the nuclei of living cells.

• Ligand is endogenous or exogenous chemical agent that binds

to a receptor.

• Binding domain is a general region on a receptor where a

ligand binds to.

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Receptors: Introduction
• To bind to its receptor, a ligand must have stereoelectronic
structure complementary to that of the receptor’s
stereoelectronic structure.

• Binding event either cause a positive or negative biological

response.

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Receptors: Introduction
• Binding of a drug to a receptor either inhibits the action of the
receptor or stimulates the receptor to give the physiological
responses.

• Agonist: Drug that bind to a receptor and give a similar

response to that of the endogenous ligand.

• Antagonist: drugs that bind to a receptor but do not cause a

response.

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Receptors: Introduction
• Binding forces of a drug to a receptor include: covalent
bonding, ionic bonding and dipole–dipole interactions of all
types, including hydrogen bonding, charge-transfer bonding,
hydrophobic bonding and van der Waals’ forces.

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Receptors: Introduction
• Binding of many drugs to their receptors is by weak reversible
interactions:

• Binding of a drug to its receptor is concentration dependent:

– High [Drug]  Formation of the complex  Drug action
– Low [Drug]  Dissociation of the complex  Drug metabolism and
excretion.

• Drugs can form strong bonds with their receptors  not

readily dissociate from the receptor when their
concentrations in the extracellular fluid fall  have a long
duration of action.

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Receptors: Introduction
• Binding of many drugs to their receptors is by weak reversible
interactions:

• Drug = Ligand (L) ; Receptor (R); Receptor-Ligand complex (RL)

• Dissociation constant: Kd = koff/kon

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Receptors: Introduction
• The dissociation of the complex can be described by:

(1)

If the total concentration of the receptor RT = [RL] + [R], then (1)

becomes:

[RL]/RT: fraction of the receptors that have a bound ligand.

 Lower Kd  higher affinity the receptor has for its ligand.
 [L] = Kd  [RL]= 0.5 RT
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Receptors: Introduction
• Neurotransmitters: chemical messengers that bind and
interacts with a specific receptor embedded in the cell
membrane leading to a series or cascade of secondary
effects, which results either in a flow of ions across the cell
membrane or in the switching on (or off ) of enzymes inside
the target cell.

• Hormones: receptors also receive chemical messages from

circulating hormones receptors are responsible for binding
these messengers and triggering a series of secondary effects.

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Receptors: Introduction

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Receptors: Introduction
• Neurotransmitters and hormones:
– simple molecules, such as monoamines (e.g. acetylcholine,
noradrenaline, dopamine, and serotonin)
– amino acids (γ-aminobutyric acid, glutamic acid, and glycine)
– Ions: Ca2+, Na+
– Complex chemical messengers: lipids (prostaglandins); purines
(adenosine, ATP; neuropeptides (endorphins and enkephalins,
enzymes.

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Receptors: Introduction
• Second messengers:
– The binding of ligands (“first messengers”) to many cell surface
receptors leads to a short lived increase (or decrease) in the
concentration of certain low-molecular-weight intracellular signaling
molecules termed second messengers.
– Common second messengers: cAMP, cGMP, DAG, IP3

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Receptors: Introduction
• Second messengers:
– The binding of ligands (“first messengers”) to many cell surface
receptors leads to a short lived increase (or decrease) in the
concentration of certain low-molecular-weight intracellular signaling
molecules termed second messengers.
– Common second messengers: cAMP, cGMP, DAG, IP3

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Receptors: classifications
• Classified into 4 superfamilies:
– Ion channels
– G-coupled proteins
– Kinase –linked
– Intracellular

• Members of a superfamily share the same general structure

and mechanism of action but could have variations in amino
acid sequences and sizes of their extracellular and
intracellular domains.

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Receptors: classifications
• Each of the superfamilies is subdivided into a number of types
of receptor whose members are usually defined by their
endogenous ligand.
– Ex. receptors that bind acetylcholine (ACh)  cholinergic
type; those that receptors bind adrenaline and
noradrenaline adrenergic type.

• Subtypes classified by genetic code responsible for their

structure or by the exogenous ligands that selectively bind to
the receptor.
– Ex. endogenous ligand acetylcholine will bind to all
cholinergic receptors (AChR) but exogenic ligand nicotine
will only bind to nicotinic cholinergic receptors (nAChR).

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Receptors: classifications

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Receptors: classifications

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Ion channel receptors
• Ion channels: complexes made up of 5 protein subunits which
traverse the cell membrane with hollow, hydrophilic center
lined with polar amino acids.
• Ions can cross the fatty barrier of the cell membrane by
controlled moving through these hydrophilic channels.
• Ion channels are specific for ions: cations (Na+ , K+, Ca2+) and
anion (Cl-).
•
Ion channel receptors
• Lock-gate mechanism:
– Resting state: ion channel is closed.
– Upon the binding of a messenger to the receptor binding
site  induced fit causes a conformational change of the
protein  ion channel opens
Ion channel receptors
• Structures:
– Ion channel receptors are glycoproteins.
– Protein subunits in an ion channel are not identical but
each subunit composes of 4 hydrophobic transmembrane
(TM) regions.
Ion channel receptors
• Structures:
Ion channel receptors
• Gating:
– ion channel open upon the binding of a ligand to its receptor  ligand
–gated ion channels.
– Ion channel open by a membrane potential voltage-gated ion
channels.
G-protein coupled receptors
• Introduction:
– G protein coupled receptors (GPCRs): the most important drug targets.
G-protein coupled receptors
• Introduction:
– activated by hormones and slow-acting neurotransmitters.
– include the muscarinic receptor, adrenergic receptors,
and opioid receptors.
– activate G-proteins responsible for signaling cascade.
Regulation of glycogen phosphorylase
• Epinephrine & glucagon signal the need for glycogen
degradation

Plasma
membrane

G protein
• Low energy state  AMP
• Glucagon and epinephrine trigger activates phosphorylase
cAMP cascade → initiate glycogen  glycogen degradation
degradation.
• When energy needs have been met, is on.
phosphorylase kinase &
phosphorylase are inactivated→
glycogen degradation is shut off.

Biochemistry, Tymoczko, Berge, Strayer

(inactive) (active) 26
G-protein coupled receptors
• Structures:
– GPCRs fold up back and forth through the cell membrane
seven times  7 transmembrane (TM) receptors.
– Each TM is hydrophobic and helical.
– Binding sites are located intracellular side.
G-protein coupled receptors
• Evolutionary tree of GPCRs:
– Similar overall structures but significant variation in amino acid
sequences.
– Subfamilies: class A (rhodopsin-like receptors), class B (secretin-like
receptors), and class C (metabotropic glutamate-like and pheromone
receptors).
Kinase-linked Receptors
• are a superfamily of receptors which activate enzymes directly
and do not require a G-protein.
• Tyrosine-kinase receptor: the protein plays dual role as a
receptor and an enzyme
• Kinase-linked receptors are activated by a large
number of polypeptide hormones, growth factors, and
cytokines.
Kinase-linked Receptors
• Tyrosine kinase receptors consists of:
– a single extracellular region (N-terminal chain) that includes the
binding site for the chemical messenger;
– a single hydrophobic region that traverses the membrane as an α-helix
of seven turns;
– a C-terminal chain on the inside of the cell.
Kinase-linked Receptors
• Activation of Tyrosine kinase receptors:
– Ligand binding and dimerization followed by activation:
Kinase-linked Receptors
• Activation of Tyrosine kinase receptors:
- Ligand binding only for receptors existed in
dimers/tetramers followed by activation.
Kinase-linked Receptors
• Activation of Tyrosine kinase receptors:
– Upon being dimerized, receptors not having inherent
catalytic activity can bind and activate another tyrosine
kinase from the cytoplasm.
Intracellular Receptors
• Are receptors located within the cell.
• About 50 members and are important in directly regulating
gene transcription nuclear hormone receptors or nuclear
transcription factors.
• Chemical messengers: hydrophobic  steroid hormones,
thyroid hormones, and retinoids.
• Have similar general structures:

Single protein with 2 binding sites:

• Ligand binding site at C-terminus.
• DNA binding site near the center.
Intracellular Receptors
• Mechanism:
– Messenger (ligand) crosses the cell membrane to reach its receptor
and binds to it at the ligand binding site.
– Upon the binding event causes a change in the conformation of the
receptor, leading a dimerization of the ligand-receptor complex.
– The dimer binds to a co-activator protein.
– The whole complex binds to a particular region of the cell’s DNA.

• Chemical messengers: hydrophobic  steroid hormones,

thyroid hormones, and retinoids.
• Have similar general structures:
Outlines
• Receptor structures and functions:
– Ion channels;
– G-protein coupled;
– Kinase linked; and
– Intracellular

• Signal transduction:
– G-protein coupled; and
– Kinase linked
Signal transduction pathways for G-proteins
Messenger-GPCR

Activated G-protein

Activated signalling cascade

Activated target
Signal transduction pathways for G-proteins
• G-proteins:
– are membrane-bound proteins in the cytosol.
– several types of G-protein (e.g. Gs, Gi/Go, Gq/G11) and several
subtypes of these. Specific G-proteins are recognized by specific
receptors.
– are composed of three protein subunits (α, β, and γ). The α-subunit
has a binding pocket for guanyl nucleotides.
• When binds to guanosine diphosphate (GDP): off mode
• When binds to guanosine triphosphate (GTP): on mode
Signal transduction pathways for G-proteins
• G-proteins:
• When binds to guanosine triphosphate (GTP): on mode
Signal transduction pathways for G-proteins
• G-proteins:
• When binds to guanosine triphosphate (GTP): on mode
Signal transduction pathways for G-proteins
• G-proteins:
Signal transduction pathways for G-proteins
• G-proteins:
– Different α-subunits will have different targets and effects:
• αs stimulates adenylate cyclase;

• αi inhibits adenylate cyclase and may also activate potassium ion

channels;

• αo activates receptors that inhibit neuronal calcium ion channels;

• αq activates phospholipase C.
Signal transduction involving G-proteins and adenylate cyclase

Step 1: Activation of adenylate cyclase by αs-subunit

• αs-subunit binds to adenylate cyclase (or adenylyl cyclase) &
‘switches’ it to on mode catalyzes the synthesis of cAMP, a
secondary messenger.
• synthesis of several hundred cAMP  representing
substantial amplification of the signal.
Signal transduction involving G-proteins and adenylate cyclase

Step 1: Activation of adenylate cyclase by αs-subunit

• αs-subunit binds to adenylate cyclase (or adenylyl cyclase) &
‘switches’ it to on mode catalyzes the synthesis of cAMP, a
secondary messenger.
• synthesis of several hundred cAMP  representing
substantial amplification of the signal.
Signal transduction involving G-proteins and adenylate cyclase

• αs-subunit has intrinsic GTP-ase activity --> hydrolyze GTP to

GDP and Pi -> deactivates itself after a certain time period and
returns to the off mode.
Signal transduction involving G-proteins and adenylate cyclase

Step 2: Activation of protein kinase A (PKA)

• Ex. Glycogen metabolism
• Ex. Fat degradation
Glycogen degradation & synthesis are reciprocally regulated

Low energy state AMP activates

phosphorylase  glycogen
degradation is on.

Biochemistry, Tymoczko, Berge, Strayer

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Protein phosphatase 1 reverses the enzymatic effects on glycogen metabolism

(inactive) (active) (active) (inactive)

(inactive) (active)

Biochemistry, Tymoczko, Berge, Strayer

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Lipid mobilization
• Triacylglycerol storage must be hydrolyzed to yield fatty acids:

• The reaction is triggered by glucagon and epinephrine hormones:

Biochemistry, Tymoczko, Berge, Strayer 49

Signal transduction involving G-proteins and adenylate cyclase

Gi -proteins
• Adenylate cyclase can also be inhibited by a different G
protein— the Gi-protein.
• the αi-subunit of Gi protein released binds to adenylate
cyclase and inhibits the enzyme.
• Receptors that bind Gi-proteins: muscarinic M2 receptor of
cardiac muscle, α2-adrenoceptor in smooth muscle, and
opioid receptors in the central nervous system.
• Production of cAMP is under the dual control of:
– a brake: a neurotransmitter forms a receptor–ligand complex which
activates a Gi protein
– an accelerator: a neurotransmitter forms a receptor–ligand complex
which activates a Gs protein.
Signal transduction involving G-proteins and phospholipase C

Phosphatidylinositol (PI) derived second messengers

• inositol group extending into the cytosol can be reversibly
phosphorylated at several positions by the combined actions
of various kinases and phosphatases.
Signal transduction involving G-proteins and phospholipase C

Released αq-subunit of a Gq protein activates phospholipase C

• activated phospholipase C (PLC) catalyzes the
hydrolysis of phosphatidylinositol diphosphate (PIP2)
(an integral part of the cell membrane structure) to generate
two secondary messengers diacylglycerol (DAG or DG)
and inositol triphosphate (IP3).
Signal transduction involving G-proteins and phospholipase C

Action of the second messenger DAG (DG)

• Activates protein kinase C (PKC) which catalyzes the
phosphorylation of serine or threonine of enzymes 
activate specific rxns in the cell.
Signal transduction involving G-proteins and phospholipase C

Action of the second messenger inositol triphosphate IP3

• IP3 mobilizes Ca2+  activates others Ca2+ dependent PK and
calmodulin dependent PK  phosphorylate and activate
other enzymes.

•
Signal transduction involving kinase linked receptors
Activation of signalling proteins and enzymes
• Binding of a ligand to the kinase linked receptors (tyrosine
kinase)activates the receptors by phosphorylation.
• Phosphotyrosine groups become binding sites for other
signalling proteins or enzymes.

•
Signal transduction involving kinase linked receptors
Activation of guanylate cyclase by kinase receptors
• Some kinase receptors have an intracellular active site
capable of catalyzing the formation of cGMP from
GTP.
• The membrane-bound receptor/enzyme spans the cell
membrane and has a single transmembrane segment. It has
an extracellular receptor binding site and an intracellular
guanylate cyclase active site.
• Ligands are α-atrial natriuretic peptide and brain natriuretic
peptide.
• cGMP appears to open Na+ channels in the kidney, promoting
the excretion of Na+ .
Signal transduction involving kinase linked receptors