2. Robert J. Lefkowitz
Brian K. Kobilka
1943, New York, NY, USA
Howard Hughes Medical Institute, Duke
University Medical Center, Durham, NC, USA
1955, Little Falls, MN, USA
Stanford University School of Medicine,
Stanford, CA, USA
1
5. 1901
Reactive cells have a „receptive substance‟
on their surface.
The mechanisms of the action of hormones.
1958
1971
cyclic AMP (cAMP) and adenylyl cyclase
Discovery of “G-proteins and the role of
these proteins in signal transduction in cells”.
4
6. Ⅰ.The mechanisms of the action of hormones
?
first
messenger
Cell surface
receptor
Epinephrine
adenyl
cyclase
cyclic
AMP
second
messenger
active
enzyme
Glycogen
phosphorylase
Glucose
Earl Sutherland.1958
5
7. Ⅱ.The role of G-proteins in signal transduction
Extracellular signal ——First messenger
Signal A
Cell exterior
GTP
Cell interior
Signal B
Discriminator
/Receptor
Transducers
/G-protein
Chemical
nature
GTP
Amplifier
Intracellular signal ——Second messenger
β
αγ
peptide chains
6
9. Extracellular ——The mechanisms of
the hormones are clear.
Intracellular——G-proteins, the
transduction of signals in cells is clear.
Research
Progress
Membrane——How these receptors
work in intricate detail is unclear.
How is this achieved on a molecular
level?
Key
Questions
Which molecules do the job, and how?
How are the signals discriminated, and
regulated?
7
11. Existence, Detection & Visualization
modified adrenocorticotropic hormone(ACTH) with
radioactive iodine and observed its binding to
adrenal membrane preparations
Lefkowitz RJ, et al.
Science(1970)
Proc Natl Acad Sci USA.1970
revealed the three-dimensional structure of a fully functional
ternary complex at high
resolution——the β2-adrenergic receptor (βAR)
Kobilka BK, et al. Nature.2011
9
12. The ternary complex model
Allosteric
mechanism
extracellular
ligand (agonist),
transmembrane
GPCR
&
intracellular
G-protein
Ternary complex model
Lefkowitz RL, et al. J Biol Chem.1980
10
14. Seminal contribution
cloned and sequenced the first receptor
for epinephrine, βAR.
βAR——β2-adrenergic receptor
A family
Epinephrine
There has to be a complete family of
receptors that look alike and function
homology
in the same manner!
Dopamine
——Robert Lefkowitz
βAR
Serotonin
Flavour
& odour
Light
rhodopsin
Kobilka BK, et al. Nature.1986
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15. Reflection
Face the problem
What is the significance of a research, no matter on
theoretical or on practical?
Long-term accumulation, determination
Endless works and failures.
Establish relationships
Stand on the shoulders of giants.
Making several achievements to be a theoretical system.
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