STUDIES OF

G-PROTEIN–COUPLED

RECEPTORS

the Nobel Prize in Chemistry 2012

Dec.07,2012

Brian K. KobilkaRobert J. Lefkowitz

1943, New York, NY, USA

Howard Hughes Medical Institute, Duke

University Medical Center, Durham, NC, USA

1

1955, Little Falls, MN, USA

Stanford University School of Medicine,

Stanford, CA, USA

GPCRs——G-protein–coupled receptors

The GPCRs mediate a flow of information that tells the

inside of cells about the conditions on their outside.

LigandReceptor

Protein G-protein

2

CHOLERA

cholera toxin

active form

G-protein

Na+ H2O

Smell Light

dehydration

Taste

3

Reactive cells have a „receptive substance‟

on their surface.1901

1971

The mechanisms of the action of hormones. cyclic AMP (cAMP) and adenylyl cyclase

1958

Discovery of “G-proteins and the role of

these proteins in signal transduction in cells”.

4

Ⅰ.The mechanisms of the action of hormones

Glycogen

Glucose

?

phosphorylaseEpinephrine

cyclic

AMPadenyl

cyclase

receptoractive

enzyme

Cell surface

5

second messenger

first messenger

Earl Sutherland.1958

Ⅱ.The role of G-proteins in signal transduction

Extracellular signal ——First messenger

Transducers

/G-protein

Amplifier

Intracellular signal ——Second messenger

Signal A Signal B

Cell exterior

Cell interior

GTP GTP

Chemical nature

6

αβ

γ

peptide chains

Discriminator

/Receptor

Alfred G. Gilman,Martin Rodbell.1977

6

Key

Questions

How is this achieved on a molecular

level?

Which molecules do the job, and how?

How are the signals discriminated, and

regulated?

Extracellular ——The mechanisms of

the hormones are clear.

Intracellular——G-proteins, the

transduction of signals in cells is clear.

Membrane——How these receptors

work in intricate detail is unclear.

7

Research

Progress

Groundbreaking Works

Detection

&

Visualization

8

Cloned

&

Sequenced

Model

&

Mechanism

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

Existence, Detection & Visualization

9

The ternary complex model

extracellular

ligand (agonist),

transmembrane

GPCR&

intracellular

G-protein

Lefkowitz RL, et al. J Biol Chem.1980

Ternary complex model

Allosteric

mechanism

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Conformational

changes

in

the

receptor

protein

Signalling mechanism

Hydrophobic

cleft

The structural changes result from the rearrangement of a network of interactions in the receptor.

Structural

changes

ACTIVE

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C-terminal

helix of Gα

Seminal contribution

cloned and sequenced the first receptor

for epinephrine, βAR.βAR——β2-adrenergic receptor

homologyA family

Kobilka BK, et al. Nature.198612

Epinephrine Dopamine

Serotonin Light

Flavour

& odour

βAR

rhodopsin

There has to be a complete family of receptors that look alike and function in the same manner!

——Robert Lefkowitz

Reflection

Face the problem

Stand on the shoulders of giants.

Establish relationships

Making several achievements to be a theoretical system.

Long-term accumulation, determination

What is the significance of a research, no matter on

theoretical or on practical?

Endless works and failures.

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THANKS