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

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 6 PROTEINS AS DRUG TARGETS: RECEPTOR STRUCTURE & SIGNAL TRANSDUCTION Part 2: Sections 6.3 - 6.6. Contents Part 2: Sections 6.3 - 6.6 3. G-protein-coupled receptors (7-TM receptors)

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

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  1. Patrick An Introduction to Medicinal Chemistry 3/e Chapter 6 PROTEINS AS DRUG TARGETS: RECEPTOR STRUCTURE & SIGNAL TRANSDUCTION Part 2: Sections 6.3 - 6.6

  2. Contents Part 2: Sections 6.3 - 6.6 3. G-protein-coupled receptors (7-TM receptors) 3.1. Structure - Single protein with 7 transmembrane regions 3.2. Ligands 3.3. Ligand binding site - varies depending on receptor type 3.4. Bacteriorhodopsin & rhodopsin family (2 slides) 3.5. Receptor types and subtypes (2 slides) 3.6. Signal transduction pathway a) Interaction of receptor with Gs-protein (3 slides) b) Interaction of s with adenylate cyclase (2 slides) c) Interaction of cyclic AMP with protein kinase A (PKA) (4 slides) 3.7. Glycogen metabolism - triggered by adrenaline in liver cells (2 slides) 3.8. GI proteins 3.9. Phosphorylation 3.10. Drugs interacting with cyclic AMP signal transduction 3.11. Signal transduction involving phospholipase C (PLC) (2 slides) 3.12. Action of diacylglycerol (2 slides) 3.13. Action of inositol triphosphate (2 slides) 3.14. Resynthesis of PIP2 [29 slides]

  3. C N -Terminal chain -Terminal chain NH2 Extracellular loops HO2C Transmembrane Membrane VII VI V IV III II I helix G-Protein binding region Variable Intracellular loops intracellular loop 3. G-protein-coupled receptors (7-TM receptors) 3.1 Structure - Single protein with 7 transmembrane regions

  4. 3. G-protein-coupled receptors (7-TM receptors) 3.2 Ligands • Monoamines e.g. dopamine, histamine, noradrenaline, acetylcholine (muscarinic) • Nucleotides • Lipids • Hormones • Glutamate • Ca++

  5. Ligand A B C D 3. G-protein-coupled receptors (7-TM receptors) 3.3 Ligand binding site - varies depending on receptor type A) Monoamines - pocket in TM helices B) Peptide hormones - top of TM helices + extracellular loops + N-terminal chain C) Hormones - extracellular loops + N-terminal chain D) Glutamate - N-terminal chain

  6. 3. G-protein-coupled receptors (7-TM receptors) 3.4 Bacteriorhodopsin & rhodopsin family • Rhodopsin = visual receptor • Many common receptors belong to this same family • Implications for drug selectivity depending on similarity (evolution) • Membrane bound receptors difficult to crystallise • X-Ray structure of bacteriorhodopsin solved - bacterial protein similar to rhodopsin • Bacteriorhodopsin structure used as ‘template’ for other receptors • Construct model receptors based on template and amino acid sequence • Leads to model binding sites for drug design • Crystal structure for rhodopsin now solved - better template

  7. 3. G-protein-coupled receptors (7-TM receptors) 3.4 Bacteriorhodopsin & rhodopsin family

  8. Receptor Types Subtypes Alpha (a) Adrenergic a1, a2A, a2B, a2C Beta (b) b1, b2, b3 Nicotinic Cholinergic Muscarinic M1-M5 3. G-protein-coupled receptors (7-TM receptors) 3.5 Receptor types and subtypes Reflects differences in receptors which recognise the same ligand

  9. 3. G-protein-coupled receptors (7-TM receptors) 3.5 Receptor types and subtypes • Receptor types and subtypes not equally distributed amongst tissues. • Target selectivity leads to tissue selectivity Heart muscle - b1 adrenergic receptors Fat cells - b3 adrenergic receptors Bronchial muscle - a1& b2 adrenergic receptors GI-tract - a1 a2 & b2 adrenergic receptors

  10. GS-Protein -membrane bound protein of 3 subunits (a, b, g) - aS subunit has binding site for GDP -GDP bound non covalently b g a GDP 3. G-protein-coupled receptors (7-TM receptors) 3.6 Signal transduction pathway a) Interaction of receptor with Gs-protein

  11. Ligand Ligand binding G-protein binds Cell membrane G Protein Receptor Induced fit for G-protein ß ß ß Induced fit g g g a a a GDP GTP Binding site for G-protein opens = GDP 3. G-protein-coupled receptors (7-TM receptors) 3.6 Signal transduction pathway a) Interaction of receptor with Gs-protein G-Protein alters shape GDP binding site distorted GDP binding weakened GDP departs

  12. ß g ß ß g g GTP binds Fragmentation and release a a a Binding site recognises GTP 3. G-protein-coupled receptors (7-TM receptors) 3.6 Signal transduction pathway a) Interaction of receptor with Gs-protein Induced fit G-protein alters shape Complex destabilised • Process repeated for as long as ligand bound to receptor • Signal amplification - several G-proteins activated by one ligand • as Subunit carries message to next stage

  13. GTP as-subunit GDP Adenylate cyclase Binding site for as subunit GTP hydrolysed to GDP catalysed by as subunit Binding Induced fit P ATP cyclic AMP ATP cyclic AMP Active site (open) Active site (closed) Active site (closed) Signal transduction (con) as Subunit changes shape Weaker binding to enzyme Departure of subunit Enzyme reverts to inactive state as Subunit recombines with b,g dimer to reform Gs protein 3. G-protein-coupled receptors (7-TM receptors) 3.6 Signal transduction pathway b) Interaction of as with adenylate cyclase

  14. 3. G-protein-coupled receptors (7-TM receptors) 3.6 Signal transduction pathway b) Interaction of as with adenylate cyclase • Several 100 ATP molecules converted before as-GTP deactivated • Represents another signal amplification • Cyclic AMP becomes next messenger (secondary messenger) • Cyclic AMP enters cell cytoplasm with message

  15. 3. G-protein-coupled receptors (7-TM receptors) 3.6 Signal transduction pathway c) Interaction of cyclic AMP with protein kinase A (PKA) • Protein kinase A = serine-threonine kinase • Activated by cyclic AMP • Catalyses phosphorylation of serine and threonine residues on protein substrates • Phosphate unit provided by ATP Link

  16. Kinase:Any of various enzymes that catalyze the transfer of a phosphate group from a donor, such as ADP or ATP, to an acceptor. Phosphatase: Any of numerous enzymes that catalyze the hydrolysis of esters of phosphoric acid and are important in the absorption and metabolism of carbohydrates, nucleotides, and phospholipids and in the calcification of bone. Phosphorylase: An enzyme that catalyzes the production of glucose phosphate from glycogen and inorganic phosphate.

  17. Adenylate cyclase cyclic AMP ATP Activation Protein kinase P Enzyme (inactive) Enzyme (active) Chemical reaction 3. G-protein-coupled receptors (7-TM receptors) 3.6 Signal transduction pathway c) Interaction of cyclic AMP with protein kinase A (PKA) Link

  18. cAMP catalytic subunit C C R R R R cAMP binding sites C C catalytic subunit 3. G-protein-coupled receptors (7-TM receptors) 3.6 Signal transduction pathway c) Interaction of cyclic AMP with protein kinase A (PKA) Protein kinase A- 4 protein subunits - 2 regulatory subunits (R) and 2 catalytic subunits (C) Note Cyclic AMP binds to PKA Induced fit destabilises complex Catalytic units released and activated Link

  19. C P Protein + ATP Protein + ADP 3. G-protein-coupled receptors (7-TM receptors) 3.6 Signal transduction pathway c) Interaction of cyclic AMP with protein kinase A (PKA) Phosphorylation of other proteins and enzymes Signal continued by phosphorylated proteins Further signal amplification

  20. 3. G-protein-coupled receptors (7-TM receptors) 3.7 Glycogen metabolism - triggered by adrenaline in liver cells

  21. 3. G-protein-coupled receptors (7-TM receptors) 3.7 Glycogen metabolism - triggered by adrenaline in liver cells Coordinated effect - activation of glycogen metabolism - inhibition of glycogen synthesis Adrenaline has different effects on different cells - activates fat metabolism in fat cells

  22. 3. G-protein-coupled receptors (7-TM receptors) 3.8 GI proteins • Binds to different receptors from those used by Gs protein • Mechanism of activation by splitting is identical • aI subunit binds adenylate cyclase to inhibit it • Adenylate cyclase under dual control (brake/accelerator) • Background activity due to constant levels of as and ai • Overall effect depends on dominant G-Protein • Dominant G-protein depends on receptors activated

  23. N N H H N H 3 3 3 O O O P O O Active site O O H O P open O Active site O O O closed 3. G-protein-coupled receptors (7-TM receptors) 3.9 Phosphorylation • Prevalent in activation and deactivation of enzymes • Phosphorylation radically alters intramolecular binding • Results in altered conformations

  24. 3. G-protein-coupled receptors (7-TM receptors) 3.10 Drugs interacting with cyclic AMP signal transduction Cholera toxin - constant activation of c.AMP - diahorrea Theophylline and caffeine - inhibit phosphodiesterases - phosphodiesterases responsible for metabolising cyclic AMP - cyclic AMP activity prolonged

  25. Active site (open) Active site (closed) DG a a a PLC PLC PLC IP3 Active site (closed) aq departs GTP hydrolysis DG a PIP2 PLC a PLC Phosphate IP3 enzyme deactivated 3. G-protein-coupled receptors (7-TM receptors) 3.11 Signal transduction involving phospholipase C (PLC) • Gq proteins - interact with different receptors from GS and GI • Split by same mechanism to give aq subunit • aq Subunit activates or deactivates PLC (membrane bound enzyme) • Reaction catalysed for as long as aq bound - signal amplification • Brake and accelerator PIP2 Binding weakened

  26. Phosphatidylinositol diphosphate (integral part of cell membrane) Inositol triphosphate (polar and moves into cell cytoplasm) Diacylglycerol (remains in membrane) R= long chain hydrocarbons 3. G-protein-coupled receptors (7-TM receptors) 3.11 Signal transduction involving phospholipase C (PLC)

  27. Cell membrane Enzyme (inactive) Enzyme (active) Binding site for DG DG DG DG PKC Active site closed PKC PKC Chemical reaction Cytoplasm Cytoplasm Cytoplasm PKC moves to membrane DG binds to DG binding site Induced fit opens active site 3. G-protein-coupled receptors (7-TM receptors) 3.12 Action of diacylglycerol • Activates protein kinase C (PKC) • PKC moves from cytoplasm to membrane • Phosphorylates enzymes at Ser & Thr residues • Activates enzymes to catalyse intracellular reactions • Linked to inflammation, tumour propagation, smooth muscle activity etc

  28. Bryostatin (from sea moss) 3. G-protein-coupled receptors (7-TM receptors) 3.12 Action of diacylglycerol Drugs inhibiting PKC - potential anti cancer agents

  29. 3. G-protein-coupled receptors (7-TM receptors) 3.13 Action of inositol triphosphate • IP3 - hydrophilic and enters cell cytoplasm • Mobilises Ca2+ release in cells by opening Ca2+ ion channels • Ca2+ activates protein kinases • Protein kinases activate intracellular enzymes • Cell chemistry altered leading to biological effect

  30. Cell membrane IP3 Cytoplasm Calmodulin Calcium stores Calmodulin Ca++ Ca++ Activation Activation Protein kinase Protein kinase P P Enzyme (inactive) Enzyme (active) Enzyme (inactive) Enzyme (active) Chemical reaction Chemical reaction 3. G-protein-coupled receptors (7-TM receptors) 3.13 Action of inositol triphosphate

  31. several steps IP3 + DG PIP2 Inhibition Li+ salts 3. G-protein-coupled receptors (7-TM receptors) 3.14 Resynthesis of PIP2 Lithium salts used vs manic depression

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