today: epinephrine nestles in predicted binding site of predicted human 1- adrenergic receptor....
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Today:
Epinephrine nestles in predicted binding site of predicted human 1-adrenergic receptor. [Proc. Nat. Acad. Sci. USA, 99, 12622 (2002)].
• Battery Types• Quiz• Cell Communication
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The Basics of The Basics of Extracellular Cell SignalingExtracellular Cell Signaling
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Cells can Cells can signal signal
themselves themselves ((autocrineautocrine), ), nearby cells nearby cells ((paracrineparacrine) ) or distant or distant
cells cells ((hormoneshormones).).
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A Specific Example…A Specific Example…
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A Specific Example…A Specific Example…
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Meet the Ligands…Meet the Ligands…
R + L RLDoes this need to be reversible? If so,
which direction should be favored?
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Intracellular and Extracellular Receptors
Consider Follicle Stimulating Hormone (FSH), widely used as
a fertility drug.
Do you expect this hormone to have an
intracellular or extracellular
receptor? Why? Image: Wadsworth Center, New York State Department of Health
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Intracellular and Extracellular Receptors
Surface and ribbon representation showing the crystal structure of human FSH bound to the extracellular hormone-binding domain of its receptor (FSHR-HB). FSH alpha- and beta-subunits are in green and cyan, respectively. FSHR-HB is in red. A seven-helix transmembrane domain (gray, modeled on the structure of rhodopsin) anchors the receptor in the membrane. Upon receptor binding, FSH undergoes a concerted conformational change that affects the protruding loops, which may in turn play a direct role in activation through the receptor transmembrane domain. (Image: Courtesy Qing Fan
and Wayne A. Hendrickson) 2005
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General RuleGeneral Rule
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1. Ion Channel Receptors1. Ion Channel Receptors
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Ion Channel Receptors: Remembering Ion Channel Receptors: Remembering the Sodium Potassium Pumpthe Sodium Potassium Pump
Animation?
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Ion Channel ReceptorsIon Channel Receptors
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You Try! You Try! Structure of Acetylcholine Structure of Acetylcholine (left) and Nicotine (right)(left) and Nicotine (right)
Acetylcholine ReceptorNovember 2005 Molecule of the Month by David S. Goodsell
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2. Protein 2. Protein KinasesKinases: the Insulin : the Insulin ReceptorReceptor
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3. G-Protein Linked (coupled) 3. G-Protein Linked (coupled) Receptors- GPCRsReceptors- GPCRs
Over 60% of all Over 60% of all prescription drugs on the prescription drugs on the market, (12 of the top-20) market, (12 of the top-20) selling drugs, directly or selling drugs, directly or indirectly target GPCRs indirectly target GPCRs (=>$200 billion/yr in (=>$200 billion/yr in sales)sales)
Every known GPCR is Every known GPCR is associated with at least associated with at least one commercially one commercially available drugavailable drug
Examples include Examples include Zantac® and Pepcid® Zantac® and Pepcid® (ulcers); and morphine (ulcers); and morphine (pain) (pain)
*Bio-Quant, 2001*Bio-Quant, 2001
Epinephrine nestles in predicted binding site of predicted human 1-adrenergic receptor. [Proc. Nat. Acad. Sci. USA, 99, 12622 (2002)].
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GPCR Mechanism: GPCR Mechanism: OverviewOverview
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Another Look at G Protein-Another Look at G Protein-Coupled ReceptorsCoupled Receptors
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Cytoplasmic Cytoplasmic (Intracellular(Intracellular) Receptors) Receptors
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Signal Transduction: DirectSignal Transduction: Direct
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Signal Transduction: Signal Transduction: IndirectIndirect
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Signal Transduction: Protein Kinase Signal Transduction: Protein Kinase CascadeCascade
Critical Functions:1.Amplifies Signal2.Communicates to the Nucleus3.Multiple steps provides Specificity
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Example: RASExample: RAS
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Second Second MessengerMessenger
s: s: Sutherland’Sutherland’
s s HypothesisHypothesis Small, nonprotein, Small, nonprotein, water-soluble water-soluble molecules/ions molecules/ions that relay a signalthat relay a signal
Rapidly spread a Rapidly spread a signal through the signal through the cell via diffusioncell via diffusion
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Common Second Messengers:Common Second Messengers:
Cyclic AMP (cAMP)Cyclic AMP (cAMP)
cAMP tends to bind to ion channels, opening them, and protein kinases, activating them.
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Phospholids can be hydrolized Phospholids can be hydrolized to form second messengersto form second messengers
Example: Phosphatidyl inositol-bisphosphate (PIP2)Example: Phosphatidyl inositol-bisphosphate (PIP2)
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Other Common Second Other Common Second Messengers: CaMessengers: Ca2+2+
A wave of calcium ions
spreads through an
egg in response to fertilization.
Image: http://dept.kent.edu/biology/kline/cawave.htm
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Other Other Common Common Second Second
MessengerMessengers: Cas: Ca2+2+
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Two or More Second Two or More Second Messengers May Work Messengers May Work
TogetherTogether
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Other Cool Second Other Cool Second Messengers: Nitric OxideMessengers: Nitric Oxide
““NO news is good NO news is good news.”news.”
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Other Cool Second Other Cool Second Messengers: Nitric OxideMessengers: Nitric Oxide
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Viagra…Viagra…
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Other Modes: Direct Other Modes: Direct Communication Between CellsCommunication Between Cells
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Other Modes: Direct Other Modes: Direct Communication Between CellsCommunication Between Cells