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

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]

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

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

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

4. Tyrosine kinase linked receptors 4.3 Epidermal growth factor receptor (EGF- R) EGF Inactive EGF-R monomers Cell membrane Ligand binding and dimerisation OH HO Phosphorylation ATP ADP OP PO Induced fit opens tyrosine kinase active sites 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) 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

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

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

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

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

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

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

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