L6 Receptors as Drug Targets 3 (PDF)

L6 Receptors As Drug Targets 3 – Receptor Families IOPPN/FOLSM 2023-24 Dr Jon Drug Design & Development Robbins 5BBM2016 Pharmacology Receptors as Drug Targets – 3 Rec...

L6 Receptors As Drug Targets 3 – Receptor Families IOPPN/FOLSM 2023-24 Dr Jon Drug Design & Development Robbins 5BBM2016 Pharmacology Receptors as Drug Targets – 3 Receptor Families  Learning outcomes 1. Understand that receptors can be classified by structure and function 2. Be aware that there can be subfamilies within some families 3. Be able to describe the structure of receptors in the 4 families 4. Be able to describe the function of receptors in the 4 families Overview Classification Ion channel receptors G-protein coupled receptors Intrinsic enzyme receptors DNA binding receptors Summary 2  How receptors can be classified Pharmacology – selectivity of drugs Agonist potency orders – not very useful Antagonist binding (KB) Antagonist shifts in dose response curves (pA2 Schild plots) Function – what they do Open ion channels Activate G-proteins Activate enzymes Interact with DNA Structure – what they look like Proteins Amino acid/nucleotide sequence Receptor Subfamilies Ion channel receptors Pentameric Tetrameric Trimeric G-protein coupled receptors Class A Class B Class C Etc Intrinsic enzyme receptors Tyrosine kinase receptors Particulate guanylyl cyclase DNA binding receptors 3  Ion channel receptors Also called Ionotropic Ligand gated ion channels Receptor operated ion channels Select group GABAA Glutamate (ionotropic) Glycine Nicotinic acetylcholine ATP (P2X) Serotonin (5-HT3) ZAC ZAC = zinc activated channel 4  Pentameric ion channels Plan view of whole receptor Side view of one subunit N Ligand binding C Cation Anion Na+, Ca2+ K+ Cl- Depolarises Hyperpolarises nAChR GABAA Glycine pore 5-HT3 ZAC Can be homopentamers or heteropentamers Pore = second transmembrane domain/alpha helix Ligand binding site is extracellular 5  Tetrameric ion channels Side view of one subunit Plan view of whole receptor Ligand binding N pore Ionotropic glutamate receptors NMDA receptors C AMPA receptors Kainate receptors Cations: Na+, K+ and some Ca2+ depolarises, excitatory ALWAYS heteropentamers 3 transmembrane domains with flexible pore 6  Trimeric ion channels Plan view of whole receptor Side view of one subunit Ligand binding pore ATP receptor channels P2X receptors Cations: Na+, K+, Ca2+ Depolarises, excitatory N C 3 subunits with 2 alpha helices, pore = second one. Majority of structure is extracellular 7  Quiz 1 Why are receptors no longer adequately classified by ligands? What are the four families of receptors? What are the 3 subfamilies of ion channel receptors? What are the structure common to all ion channel receptors? 1. Because more than one ligand may act on one receptor and receptors may respond to more than one ligand. 2. The receptor superfamilies are: ion channels, GPCRs, intrinsic enzyme receptors, DNA binding receptors. 3. Ion channel receptor subfamilies = pentameric, tetrameric, trimeric 4. Alpha helices 8  G-protein coupled receptors Also called Metabotropic Seven membrane spanning Serpentine 1200 genes (3-4% human genome) 67% odorant receptors Of 375 about 300 have an identified ligand About 100 “orphan” receptors in 2005 (2022 = 57) Orphan = ligand not known Subfamilies of GPCRs N Class A Ligand binding Class B G-P coupling Class C N N C Rhodopsin like Adrenoceptors X2 Dopamine Muscarinic ACh C Serotonin (except 3) Secretin like C Opioid Cannabinoid Secretin Histamine Calcitonin mGlutmate like Neuropeptide Glucagon Opsins mGluRs etc GABAB Calcium sensing Other sub families D and F 9  Class A: ligand binding site is in transmembrane domain Class B: ligand binding site is on the outside as they bind large proteins Class C: ligand binding site is in extracellular domain and they act as dimers. Intrinsic enzyme receptors Also called Ligand binding Plieotropic receptors Catalytic receptors transmembrane Include receptors for Growth factors Cytokines enzyme Insulin Simple structure 10  IER ligand binding dimerisation autophosphorylation Substrate phosphorylation PO4 PO4 PO4 PO4 These work by phosphorylation and act as dimers to form a functional receptor. Stages of intrinsic enzyme receptor activation: 1. Ligand binding 2. Dimerization 3. Autophosphorylation 4. Substrate phosphorylation 11  DNA binding receptors Also called Ligand binding Nuclear receptors Ligand activated transcription factors Zinc fingers Include receptors for Steroid hormones Dimerization Thyroid hormones domain Vitamin D Retinoic acid DNA binding receptors are activated in cytosol and translocate into the nucleus. Zinc fingers indicate that the receptor is a DNA binding receptor. 12  DNA Binding Receptors New Classification 2023 Subgroup Members Endogenous Ligands I Thyroid Hormone Rs Thyroxine hormones Retinoic Acid Rs Retinoic acids Retinoic Acid-Related Orphan Rs Orphan Peroxisome Proliferation Activated Rs Fatty acids REV-ERBs Heme Liver X Rs Oxysterols Farnsesoid X Rs Bile acids II Retinoic X Rs Retinoid compounds Chicken Ovalbumin Upstream Promoter Transcription Factors Orphan III Glucocorticoid Rs Glucocorticoids Androgen Rs Dihydrotestosterone Progesterone Rs Progesterone Estrogen Rs Estrogens Estrogen Receptor-Related Rs Orphan IV Nerve Growth Factor IB Unsaturated fatty acids Nurr-Related Factor 1 Unsaturated fatty acids Neuron-Derived Orphan R Orphan V Liver Receptor Homologue 1 Phospholipids VI Germ Cell Nuclear Factor Orphan DBR Ligand e.g steroid translocation nucleus dimerisation DNA Altered transcription Plasma membrane Stages of DNA binding receptor activation: 13  o Ligand, e.g. steroid hormone, binds to receptor. o The receptor dimerises in the cytosol. o The dimerised receptors translocate into the nucleus. o The zinc finger domain binds to the DNA to alter gene transcription. o The protein products that the cell produces are different. Only work when they get into the nucleus. Ligands of DNA binding receptors are lipophilic and can cross a plasma membrane Properties of the different Families Receptor type Ion channel GPCR Intrinsic DNA enzyme binding Structure Multiple Single protein Often dimers dimers subunits (rarely dimer) Speed of Very fast Fast Slow Very Slow response (µs-ms) (ms-s) (mins-hours) (hours-days) Amplification Low Very High High High Number of types ~10 ~1000 ~10 ~50 Different receptors allow for different speed of responses and different levels of signal amplification which enables highly specific responses. 14  Quiz 2 Which family of receptors has the largest number of types? What is an orphan receptor? After ligand binding what is the next step in activation of Intrinsic Enzyme Receptors What is the special requirement for the ligands of DNA Binding Receptors 1. GPCRs have the largest number of types. 2. An orphan receptor is a receptor with a known structure that does not have a known ligand. 3. Following ligand binding, intrinsic enzyme receptors dimerise. 4. Ligands of DNA binding receptors must be lipophilic so they can pass through the plasma membrane. 15  References Rang, Dale, Ritter & Flower & Henderson Pharmacology 7th edition chapter 3. 16