Patrick An Introduction to Medicinal Chemistry 3e Chapter

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 6 PROTEINS AS DRUG TARGETS: RECEPTOR STRUCTURE & SIGNAL TRANSDUCTION Part 3: Section 6. 7 © 1

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] © 1

4. Tyrosine kinase linked receptors • Bi-functional receptor / enzyme • Activated by hormones • Over-expression can result in cancer © 1

4. Tyrosine kinase linked receptors 4. 1 Structure Extracellular N-terminal chain Ligand binding region N H 2 Hydrophilic transmembrane region (a-helix) Cell membrane Catalytic binding region (closed in resting state) Intracellular C-terminal chain C O 2 H © 1

4. Tyrosine kinase linked receptors 4. 2 Reaction catalysed by tyrosine kinase Tyrosine kinase Mg++ O Protein N C Protein OH Tyrosine residue ATP ADP O Protein N C Protein O Phosphorylated tyrosine residue © 1 P

4. Tyrosine kinase linked receptors 4. 3 Epidermal growth factor receptor (EGF- R) EGF Ligand binding and dimerisation Cell membrane Phosphorylation OH HO OH Inactive EGF-R monomers OH OP PO ATP ADP OP Induced fit opens tyrosine kinase active sites Link Binding site for EGF - protein hormone - bivalent ligand Active site of tyrosine kinase Link © 1 OP

Link © 1

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 © 1

4. Tyrosine kinase linked receptors 4. 4 Insulin receptor (tetrameric complex) Insulin Phosphorylation Cell membrane HO OH OH OH ATP ADP PO OP OP Kinase active site opened by induced fit Insulin binding site Kinase active site © 1 OP

http: //www. vivo. colostate. edu/hbooks/pathphys/endocrine/moaction/surface. html Link © 1

4. Tyrosine kinase linked receptors 4. 5 Growth hormone receptor Tetrameric complex constructed in presence of growth hormone GH GH binding & dimerisation Activation and phosphorylation Binding of kinases GH receptors (no kinase activity) ATP HO kinases OH HO OH OH OH ADP PO OP Kinase active site opened by induced fit Growth hormone binding site Kinase active site © 1 OP OP

4. Tyrosine kinase linked receptors 4. 6 Signalling pathways Ligand P P P Ligand P P signalling protein © 1

4. Tyrosine kinase linked receptors 4. 6 Signalling pathways 1 -TM Receptors Tyrosine kinase inherent or associated Guanylate cyclase Signalling proteins PLCg IP 3 DG Ca++ PKC IP 3 kinase GAP c. GMP Grb 2 Others PIP 3 © 1

4. Tyrosine kinase linked receptors 4. 6 Signalling pathways Receptor binding site GROWTH FACTOR RECEPTOR Tyrosine kinase active site (inactive) HO OH © 1

4. Tyrosine kinase linked receptors 4. 6 Signalling pathways Growth factor 1) Binding of growth factor Dimerisation Phosphorylation 2) Conformational change HO HO HO OH OHHO PO OH OH PO PO OP OPPO Binding Ras and Grb 2 Binding and phosphorylation of Grb 2 HO OH OH PO PO PO OP OPPO Grb 2 OP OP OP GTP/GDP exchange OP PO PO PO OP OPPO GDP GTP Ras OP OP © 1 OP OP

4. Tyrosine kinase linked receptors 4. 6 Signalling pathways Gene transcription OP Ras PO PO PO OP OP Raf (inactive) Raf (active) Mek (inactive) Mek (active) Map kinase (inactive) Map kinase (active) Transcription factor (inactive) Transcription factor (active) © 1

http: //www. bioinformaticscourses. com/ISB/sp 2003/1 FMK/mechanism. html © 1

http: //faculty. plattsburgh. edu/donald. slish/tyrosinekinase/TK 1. html © 1

Assigned Reading: An Introduction to Medicinal Chemistry by Graham Patrick, Chapter 6, pp 90 -116. © 1

Homework Questions: Briefly describe three different families of membranebount receptors, including the relative speed of signal transduction. Briefly describe the mechanism whereby a typical GPCR exerts its effect. © 1