Patrick An Introduction to Medicinal Chemistry 3/e Chapter 6 PROTEINS AS DRUG TARGETS:

1. Patrick An Introduction to Medicinal Chemistry 3/e Chapter 6 PROTEINS AS DRUG TARGETS: RECEPTOR STRUCTURE & SIGNAL TRANSDUCTION Part 3: Section 6.7

2. Contents Part 3: Section 6.7 4. Tyrosine kinase linked receptors 4.1. Structure 4.2. Reaction catalysed by tyrosine kinase 4.3. Epidermal growth factor receptor (EGF- R) (2 slides) 4.4. Insulin receptor (tetrameric complex) 4.5. Growth hormone receptor 4.6. Signalling pathways (5 slides) [9 slides]

3. 4. Tyrosine kinase linked receptors • Bi-functional receptor / enzyme • Activated by hormones • Over-expression can result in cancer

4. Ligand binding region N H 2 Hydrophilic transmembrane region (a-helix) Cell membrane C O H 2 Catalytic binding region (closed in resting state) 4. Tyrosine kinase linked receptors 4.1 Structure Extracellular N-terminal chain Intracellular C-terminal chain

5. Tyrosine kinase O O C C N N Protein Protein Protein Protein Mg++ ATP ADP OH O P Tyrosine residue Phosphorylated tyrosine residue 4. Tyrosine kinase linked receptors 4.2 Reaction catalysed by tyrosine kinase

6. EGF Ligand binding Phosphorylation and dimerisation Cell membrane OH HO OP PO OH OH OP OP ATP ADP Inactive EGF-R monomers Binding site for EGF EGF - protein hormone - bivalent ligand Active site of tyrosine kinase 4. Tyrosine kinase linked receptors 4.3 Epidermal growth factor receptor (EGF- R) Induced fit opens tyrosine kinase active sites

7. 4. Tyrosine kinase linked receptors 4.3 Epidermal growth factor receptor (EGF- R) • Active site on one half of dimer catalyses phosphorylation of Tyr residues on other half • Dimerisation of receptor is crucial • Phosphorylated regions act as binding sites for further proteins and enzymes • Results in activation of signalling proteins and enzymes • Message carried into cell

8. Insulin Phosphorylation Cell membrane HO OH PO OP OP ADP ATP OP OH OH Insulin binding site Kinase active site 4. Tyrosine kinase linked receptors 4.4 Insulin receptor (tetrameric complex) Kinase active site opened by induced fit

9. GH GH binding & dimerisation Binding Activation and of kinases phosphorylation GH receptors (no kinase activity) ATP ADP PO HO OH OP OP OH OP OH kinases HO OH OH OH Growth hormone binding site Kinase active site 4. Tyrosine kinase linked receptors 4.5 Growth hormone receptor Tetrameric complex constructed in presence of growth hormone Kinase active site opened by induced fit

10. Ligand Ligand P P P P P P P P P P signalling protein 4. Tyrosine kinase linked receptors 4.6 Signalling pathways

11. 1-TM Receptors Tyrosine kinase inherent or associated Guanylate cyclase Signalling proteins cGMP PLCg IP3 kinase GAP Grb2 Others IP3 DG PIP3 Ca++ PKC 4. Tyrosine kinase linked receptors 4.6 Signalling pathways

12. Receptor binding site GROWTH FACTOR RECEPTOR Tyrosine kinase active site (inactive) HO OH HO OH 4. Tyrosine kinase linked receptors 4.6 Signalling pathways

13. Growth factor 1) Binding of growth factor 2) Conformational change Dimerisation Phosphorylation PO PO PO PO PO PO HO HO HO HO OP OP OP OP OP OP OH OH OH OH PO PO PO PO PO PO HO HO HO HO OP OP OP OP OP OP OH OH OH OH OH Binding Ras and GTP/GDP exchange Grb2 OP OP GDP GTP Ras Binding and phosphorylation of Grb2 Grb2 4. Tyrosine kinase linked receptors 4.6 Signalling pathways

14. Ras Gene transcription PO PO OP OP Raf (inactive) Raf (active) PO PO OP OP Mek (inactive) Mek (active) OP Map kinase (inactive) Map kinase (active) Transcription factor (inactive) Transcription factor (active) 4. Tyrosine kinase linked receptors 4.6 Signalling pathways