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 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) 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]

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

2. Ion channel receptors (Ligand gated ion channels) 2.1 General structure Binding site Receptor Messenger Cell membrane Cell membrane INDUCED FIT ‘GATING’ (ion channel opens) 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

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

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

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

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

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

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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