Transcript Essential Biochemistry

Signaling via Ligand-Receptor
Binding
Agonist - ligand binding to a
receptor and eliciting a response
O
H3C
O
CH3
N
N
N
N
CH3
Antagonist - ligand binding
to a receptor but not
eliciting a response
R + L ↔ R∙L
Kd = [R][L]/[R∙L]
Bacterial Quorum Sensing
Increased cell density dependant
signaling
Activation of Bio-film formation
which affects bacterial resistance
Extracellular Signals
G Protein Coupled Receptors
Guanyl nucleotide binding protein:
Minus ligand, α, β, and γ subunits
associated with GDP (inactive
bound form) and
Plus ligand, α subunit exchanges
for GTP (active released form)
Signal propagation:
Activate adenylate cyclase converts
ATP to cyclic ATP
Signal resetting:
GTP hydrolyzed to GDP and β, and γ
subunits re-associate
G-Protein Cycle and
Generation of Cyclic AMP
How is adenylate cyclase activated?
External Signal for G-Protein Activation
β2-adreneric receptor
Heterotrimeric G Protein
α, β, and γ
subunits (blue,
green, and
yellow,
respectively)
associated with
GDP (orange)
G-Protein Pathway Activation by Epinephrine
What is effective signaling?
Specificity? Sensitivity?
Adenylate Cyclase Activation/Deactivation
Cyclic AMP Deactivation
Protein Kinase A Activation by cAMP
Protein Kinase A Regulation
by Phosphorylation
Dephosphorylation blocks
substrate from
active site
Catalytic subunit:
light green
Activation loop:
dark green
Substrate target
protein: blue
External Signal for G-Protein Activation
α-adreneric receptor is also
activated by epinephrine
and norepinephrine
IP3, a product of
phosphatidylinositol
bisphosphate
hydrolysis signals a
calcium influx and
protein kinase C
activation
Phosphoinositide Cascade
Calcium Binding Protein:
Calmodulin
+2
Ca
ions
EF-hand protein family
Extended unbound
form
Bent bound to a
target protein
Receptor Tyrosine Kinases
Operative for certain
hormones and signaling
molecules that regulate
growth (e.g. insulin)
Ligand binding allows
the receptor monomer
to form a dimer unit
with cytoplasmic kinase
domain catalytically
active
Insulin receptor
Insulin
binding
site
Insulin
binding
site
Extracellular
region
Cell surface
α,β subunits: one in spacefilling (red) and other in
backbone-trace form (yellow)
Insulin Receptor Tyrosine Kinase Activation
Inactive form (blue)
Activation loop (dark blue)
Active form (green)
Activation loop (dark green)
Note:
Activation loop swings
out with Tyr phosphorylation
Ras Signal Transduction Pathway
Ras- rat sarcoma virus
Color coding: red inactive; green active
Ras Signal Transduction Pathway
Ras Signal Transduction Pathway
Protein
phosphorylation
can lead to
subsequent gene
activation
Lipid Hormone Signaling
Includes thyroid
hormones that stimulate
metabolism (right) as well
as hormones for salt,
water and reproductive
functions
Do not bind to cell-surface
receptors
Directly cross membranes
to interact with
intracellular receptors
Lipid Hormones: Eicosanoids
Regulation of blood
pressure, blood
coagulation, inflammation,
pain and fever
Aspirin inhibits
cyclooxygenase activity
and therefore serve as a
blood thinner