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

1 © Contents 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 © 1. Receptor superfamilies ION CHANNEL RECEPTORSION CHANNEL RECEPTORS G-PROTEIN COUPLED RECEPTORSG-PROTEIN COUPLED RECEPTORS KINASE LINKED RECEPTORSKINASE LINKED RECEPTORS INTRACELLULAR RECEPTORSINTRACELLULAR RECEPTORS MEMBRANEBOUND RESPONSETIMEmsecssecondsminutes

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

1 © Transverse view (nicotinic receptor) Two ligand binding sites mainly on  -subunits      Ion channel  x  subunits Cell membrane     Bindingsites 2. Ion channel receptors (Ligand gated ion channels)

1 © Transverse view (glycine receptor) Three ligand binding sites on  -subunits      Ion channel  x  x  subunits Cell membrane     Bindingsites 2. Ion channel receptors (Ligand gated ion channels)

1 © 2.2 Structure of protein subunits (4-TM receptor subunits) Extracellular loop Intracellularloop Variable loop Neurotransmitter binding region 4 Transmembrane (TM) regions (hydrophobic) H 2 N CO 2 H TM1TM2TM4TM3 Cellmembrane 2. Ion channel receptors (Ligand gated ion channels)

1 © 2.3 Detailed structure of ion channel Protein subunits Transmembrane regions Note: TM2 of each protein subunit ‘lines’ the central pore TM4 TM3 TM2 TM1 TM4 2. Ion channel receptors (Ligand gated ion channels)

1 © 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 2. Ion channel receptors (Ligand gated ion channels)

1 © 2.4 Gating Fast response measured in msecFast response measured in msec Ideal for transmission between nervesIdeal for transmission between nerves Binding of messenger leads directly to ion flows across cell membraneBinding of messenger leads directly to ion flows across cell membrane Ion flow = secondary effect (signal transduction)Ion flow = secondary effect (signal transduction) Ion concentration within cell altersIon concentration within cell alters Leads to variation in cell chemistryLeads to variation in cell chemistry 2. Ion channel receptors (Ligand gated ion channels)