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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 1: Sections 6.1 - 6.2. Contents Part 1: Sections 6.1 - 6.2 1. Receptor superfamilies 2. Ion channel receptors (Ligand gated ion channels)

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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 1: Sections 6.1 - 6.2

  2. Contents Part 1: Sections 6.1 - 6.2 1. Receptor superfamilies 2. Ion channel receptors (Ligand gated ion channels) 2.1. General structure (3 slides) 2.2. Structure of protein subunits (4-TM receptor subunits) 2.3. Detailed structure of ion channel 2.4. Gating (2 slides) [9 slides]

  3. RESPONSE TIME msecs seconds minutes MEMBRANE BOUND 1. Receptor superfamilies • ION CHANNEL RECEPTORS • G-PROTEIN COUPLED RECEPTORS • KINASE LINKED RECEPTORS • INTRACELLULAR RECEPTORS

  4. Binding site Receptor Messenger Cell INDUCED FIT ‘GATING’ (ion channel opens) Cell membrane membrane 2. Ion channel receptors (Ligand gated ion channels) 2.1 General structure Five glycoprotein subunits traversing cell membrane Cationic ion channels for K+, Na+, Ca2+ (e.g. nicotinic) = excitatory Anionic ion channels for Cl- (e.g. GABAA) = inhibitory

  5. Binding sites Ion channel a b a g g a b d a d Cell membrane Two ligand binding sites mainly on a-subunits 2. Ion channel receptors (Ligand gated ion channels) Transverse view (nicotinic receptor) 2xa, b, g, d subunits

  6. Binding sites Ion channel a a b a b b a a a b Cell membrane Three ligand binding sites on a-subunits 2. Ion channel receptors (Ligand gated ion channels) Transverse view (glycine receptor) 3xa, 2x b subunits

  7. Neurotransmitter binding region H N 2 Extracellular loop C O H 2 Cell membrane TM1 TM2 TM3 TM4 Intracellular loop Variable loop 2. Ion channel receptors (Ligand gated ion channels) 2.2 Structure of protein subunits (4-TM receptor subunits) 4 Transmembrane (TM) regions (hydrophobic)

  8. Protein subunits TM4 TM1 TM3 TM2 TM1 TM3 TM2 TM2 TM4 TM4 Transmembrane regions TM3 TM1 TM3 TM2 TM2 TM1 TM4 TM1 TM3 TM4 2. Ion channel receptors (Ligand gated ion channels) 2.3 Detailed structure of ion channel Note: TM2 of each protein subunit ‘lines’ the central pore

  9. Neurotransmitter binds Induced fit at binding site ‘Domino effect’ Rotation of 2TM regions of each protein subunit TM2 Cell Ion flow membrane TM2 TM2 TM2 TM2 TM2 TM2 TM2 Transverse view of TM2 subunits Transverse view of TM2 subunits TM2 TM2 TM2 TM2 Closed Open 2. Ion channel receptors (Ligand gated ion channels) 2.4 Gating

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  12. 2. Ion channel receptors (Ligand gated ion channels) 2.4 Gating • Fast response measured in msec • Ideal for transmission between nerves • Binding of messenger leads directly to ion flows across cell membrane • Ion flow = secondary effect (signal transduction) • Ion concentration within cell alters • Leads to variation in cell chemistry

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