Receptors Structure and Function

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Receptors Structure and Function

• Chapter 4

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The role of the receptor

• Globular proteins
• Located mostly in the cell membrane
• Receive messages from chemical messengers coming
  from other cells (CNS)
• 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

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The Role of the receptor
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The Role of the receptor

• Neurotransmitters Chemicals released from nerve
  endings which travel across a nerve synapse to
  bind with receptors on target cells, such as
  muscle cells or another nerve. Usually short
  lived and responsible for messages between
  individual cells
• Hormones Chemicals released from cells or glands
  and which travel some distance to bind with
  receptors on target cells throughout the body
• Note Chemical messengers switch on receptors
  without undergoing a reaction

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The role of the receptor

• Receptors contain a binding site (hollow or cleft
  on the receptor surface) that is recognised by
  the chemical messenger
• Binding of the messenger involves intermolecular
  bonds
• Binding results in an induced fit of the receptor
  protein
• Change in receptor shape results in a domino
  effect
• Domino effect is known as signal transduction,
  leading to a chemical signal being received
  inside the cell
• Chemical messenger does not enter the cell. It
  departs the receptor unchanged and is not
  permanently bound

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The Binding Site
Receptor
Cell
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The Binding Site

• A hydrophobic hollow or cleft on the receptor
  surface - equivalent to the active site of an
  enzyme
• Accepts and binds a chemical messenger
• Contains amino acids which bind the messenger
• No reaction or catalysis takes place

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The Binding Site

• Binding site is nearly the correct shape for the
  messenger
• Binding alters the shape of the receptor
  (induced fit)
• Altered receptor shape leads to further effects
  - signal transduction

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How does the Binding Site Change Shape?

• Before
• Intermolecular bonds not optimum length for
  maximum binding strength
• After
• Intermolecular bond lengths optimised

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Induced Fit

• Binding interactions must be strong enough to
  hold the messenger sufficiently long for signal
  transduction to take place
• Interactions must be weak enough to allow the
  messenger to depart
• Implies a fine balance
• Designing molecules with stronger binding
  interactions results in drugs that block the
  binding site - antagonists

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Main Types of Receptors

• ION CHANNEL RECEPTORS
• G-PROTEIN-COUPLED RECEPTORS
• KINASE-LINKED RECEPTORS
• INTRACELLULAR RECEPTORS

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Ion Channel Receptors

• Receptor protein is part of an ion channel
  protein complex
• Receptor binds a messenger leading to an induced
  fit
• Ion channel is opened or closed
• Ion channels are specific for specific ions
  (Na, Ca2, Cl-, K)
• Ions flow across cell membrane down
  concentration gradient
• Polarises or depolarises nerve membranes
• Activates or deactivates enzyme catalysed
  reactions within cell

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Ion Channel Receptors
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Ion Channel Receptors

• Transmembrane Proteins
• TM2 of each protein subunit lines the central
  pore

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Gating
Five glycoprotein subunits traversing cell
membrane
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gating

• Chemical messenger binds to receptor binding site
• Induced fit results in further conformational
  changes
• TM2 segments rotate to open central pore

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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

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G-PROTEIN-COUPLED RECEPTORS

• Receptor binds a messenger leading to an induced
  fit
• Opens a binding site for a signal protein
  (G-protein)
• G-protein binds, is destabilised then split

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G-PROTEIN-COUPLED RECEPTORS

• G-protein subunit activates membrane bound
  enzyme
• Binds to allosteric binding site
• Induced fit results in opening of active site
• Intracellular reaction catalysed

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G-PROTEIN-COUPLED RECEPTORS
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LIGAND BINDING SITE - varies depending on
receptor type
A) Monoamines pocket in TM helices B) Peptide
hormones top of TM helices extracellular
loops N-terminal chain C) Hormones
extracellular loops N-terminal chain D)
Glutamate N-terminal chain
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Bacteriorhodopsin Rhodopsin Family

• Rhodopsin visual receptor
• Many common receptors belong to this same family
• Implications for drug selectivity depending on
  similarity (evolution)
• Membrane bound receptors difficult to
  crystallise
• X-Ray structure of bacteriorhodopsin solved -
  bacterial protein similar to rhodopsin
• Bacteriorhodopsin structure used as template
  for other receptors
• Construct model receptors based on template and
  amino acid sequence
• Leads to model binding sites for drug design
• Crystal structures for rhodopsin and
  b2-adrenergic receptors now solved - better
  templates

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Bacteriorhodopsin Rhodopsin Family
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RECEPTOR TYPES AND SUBTYPES

• Receptor types and subtypes not equally
  distributed amongst tissues.
• Target selectivity leads to tissue selectivity

Heart muscle b1 adrenergic receptors Fat
cells b3 adrenergic receptors Bronchial
muscle a1 b2 adrenergic receptors GI-tract
a1 a2 b2 adrenergic receptors
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Tyrosine kinase - linked receptors

• Bifunctional receptor / enzyme
• Activated by hormones
• Overexpression can result in cancer

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Tyrosine kinase-linked receptors

• Protein serves dual role - receptor plus enzyme
• Receptor binds messenger leading to an induced
  fit
• Protein changes shape and opens active site
• Reaction catalysed within cell
• Overexpression related to several cancers

active site open
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Tyrosine kinase-linked receptors
Extracellular N-terminal chain
Intracellular C-terminal chain
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Reaction catalysed by tyrosine kinase
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Epidermal growth factor receptor (EGF- R)
Induced fit opens tyrosine kinase active sites
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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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Insulin receptor (tetrameric complex)
Kinase active site opened by induced fit
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Growth hormone receptor Tetrameric complex
constructed in presence of growth hormone
Kinase active site opened by induced fit
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Intracellular receptors

• Chemical messengers must cross cell membrane
• Chemical messengers must be hydrophobic
• Example-steroids and
• steroid receptors

Zinc fingers contain Cys residues (SH) Allow S-Zn
interactions
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Intracellular receptor Mechanism
7. Protein synthesis activated or inhibited
4. Binds co-activator protein