today: epinephrine nestles in predicted binding site of predicted human 1- adrenergic receptor....
TRANSCRIPT
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
The Basics of The Basics of Extracellular Cell SignalingExtracellular Cell Signaling
Cells can Cells can signal signal
themselves themselves ((autocrineautocrine), ), nearby cells nearby cells ((paracrineparacrine) ) or distant or distant
cells cells ((hormoneshormones).).
A Specific Example…A Specific Example…
A Specific Example…A Specific Example…
Meet the Ligands…Meet the Ligands…
R + L RLDoes this need to be reversible? If so,
which direction should be favored?
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
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
General RuleGeneral Rule
1. Ion Channel Receptors1. Ion Channel Receptors
Ion Channel Receptors: Remembering Ion Channel Receptors: Remembering the Sodium Potassium Pumpthe Sodium Potassium Pump
Animation?
Ion Channel ReceptorsIon Channel Receptors
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
2. Protein 2. Protein KinasesKinases: the Insulin : the Insulin ReceptorReceptor
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)].
GPCR Mechanism: GPCR Mechanism: OverviewOverview
Another Look at G Protein-Another Look at G Protein-Coupled ReceptorsCoupled Receptors
Cytoplasmic Cytoplasmic (Intracellular(Intracellular) Receptors) Receptors
Signal Transduction: DirectSignal Transduction: Direct
Signal Transduction: Signal Transduction: IndirectIndirect
Signal Transduction: Protein Kinase Signal Transduction: Protein Kinase CascadeCascade
Critical Functions:1.Amplifies Signal2.Communicates to the Nucleus3.Multiple steps provides Specificity
Example: RASExample: RAS
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
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.
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)
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
Other Other Common Common Second Second
MessengerMessengers: Cas: Ca2+2+
Two or More Second Two or More Second Messengers May Work Messengers May Work
TogetherTogether
Other Cool Second Other Cool Second Messengers: Nitric OxideMessengers: Nitric Oxide
““NO news is good NO news is good news.”news.”
Other Cool Second Other Cool Second Messengers: Nitric OxideMessengers: Nitric Oxide
Viagra…Viagra…
Other Modes: Direct Other Modes: Direct Communication Between CellsCommunication Between Cells
Other Modes: Direct Other Modes: Direct Communication Between CellsCommunication Between Cells