The Nobel Prize in Chemistry 2012


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A brief introduction of the Nobel Prize of Chemistry in 2012.

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The Nobel Prize in Chemistry 2012

  1. 1. STUDIES OF G-PROTEIN–COUPLED RECEPTORS the Nobel Prize in Chemistry 2012 Dec.07,2012
  2. 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
  3. 3. GPCRs——G-protein–coupled receptors Receptor Protein G-protein Ligand The GPCRs mediate a flow of information that tells the inside of cells about the conditions on their outside. 2
  4. 4. Smell Light cholera toxin Taste Na+ H2O G-protein CHOLERA active form dehydration 3
  5. 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. 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. 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
  8. 8. Alfred G. Gilman,Martin Rodbell.1977 6
  9. 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
  10. 10. Groundbreaking Works Detection & Visualization Cloned & Sequenced Model & Mechanism 8
  11. 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. 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
  13. 13. Signalling mechanism ACTIVE Structural changes Conformational changes in the receptor protein C-terminal helix of Gα Hydrophobic cleft The structural changes result from the rearrangement of a network of interactions in the receptor. 11
  14. 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 12
  15. 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. 13
  16. 16. THANKS