The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15537. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15537. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
The authors state that there are no conflicts of interest to disclose.
Table of contents
S1 Introduction and Other Protein TargetsS8 Adiponectin receptorsS9 Aryl hydrocarbon receptorS10 Non‐enzymatic BRD containing proteinsS11 CD moleculesS13 Methyllysine reader proteinsS14 Fatty acid‐binding proteinsS16 Notch receptorsS17 Regulators of G protein Signaling (RGS) proteinsS17 RZ familyS18 R4 familyS19 R7 familyS19 R12 familyS20 Sigma receptorsS21 TransthyretinS22 TubulinsS23 SARS‐CoV‐2S23 Structural proteinsS24 PolyproteinsS24 ProteasesS25 Nucleic acid turnoverS25 Other proteinsS27 G protein‐coupled receptorsS31 Orphan and other 7TM receptorsS32 Class A OrphansS41 Class C OrphansS41 Opsin receptorsS42 Taste 1 receptorsS43 Taste 2 receptorsS44 Other 7TM proteinsS45 5‐Hydroxytryptamine receptorsS48 Acetylcholine receptors (muscarinic)S50 Adenosine receptorsS52 Adhesion Class GPCRsS55 AdrenoceptorsS59 Angiotensin receptorsS60 Apelin receptorS61 Bile acid receptorS62 Bombesin receptorsS63 Bradykinin receptorsS64 Calcitonin receptorsS66 Calcium‐sensing receptorS67 Cannabinoid receptorsS68 Chemerin receptorsS69 Chemokine receptorsS73 Cholecystokinin receptorsS74 Class Frizzled GPCRsS76 Complement peptide receptorsS78 Corticotropin‐releasing factor receptorsS79 Dopamine receptorsS81 Endothelin receptorsS82 G protein‐coupled estrogen receptorS83 Formylpeptide receptorsS84 Free fatty acid receptorsS86 GABAB receptorsS87 Galanin receptorsS89 Ghrelin receptorS90 Glucagon receptor familyS91 Glycoprotein hormone receptorsS92 Gonadotrophin‐releasing hormone receptorsS93 GPR18, GPR55 and GPR119S94 Histamine receptorsS96 Hydroxycarboxylic acid receptorsS97 Kisspeptin receptorS98 Leukotriene receptorsS100 Lysophospholipid (LPA) receptorsS101 Lysophospholipid (S1P) receptorsS103 Melanin‐concentrating hormone receptorsS104 Melanocortin receptorsS105 Melatonin receptorsS106 Metabotropic glutamate receptorsS108 Motilin receptorS110 Neuromedin U receptorsS111 Neuropeptide FF/neuropeptide AF receptorsS112 Neuropeptide S receptorS113 Neuropeptide W/neuropeptide B receptorsS114 Neuropeptide Y receptorsS116 Neurotensin receptorsS117 Opioid receptorsS119 Orexin receptorsS120 Oxoglutarate receptorS120 P2Y receptorsS123 Parathyroid hormone receptorsS124 Platelet‐activating factor receptorS125 Prokineticin receptorsS126 Prolactin‐releasing peptide receptorS127 Prostanoid receptorsS129 Proteinase‐activated receptorsS131 QRFP receptorS132 Relaxin family peptide receptorsS134 Somatostatin receptorsS135 Succinate receptorS136 Tachykinin receptorsS137 Thyrotropin‐releasing hormone receptorsS138 Trace amine receptorS139 Urotensin receptorS140 Vasopressin and oxytocin receptorsS142 VIP and PACAP receptorsS157 Ion channelsS159 Ligand‐gated ion channelsS160 5‐HT3 receptorsS162 Acid‐sensing (proton‐gated) ion channels (ASICs)S165 Epithelial sodium channel (ENaC)S166 GABA
receptorsS172 Glycine receptorsS175 Ionotropic glutamate receptorsS180 IP3 receptorsS181 Nicotinic acetylcholine receptorsS185 P2X receptorsS187 ZACS188 Voltage‐gated ion channelsS188 CatSper and Two‐Pore channelsS190 Cyclic nucleotide‐regulated channelsS192 Potassium channelsS193 Calcium‐ and sodium‐activated potassium channelsS195 Inwardly rectifying potassium channelsS199 Two‐pore domain potassium channelsS201 Voltage‐gated potassium channelsS204 Ryanodine receptorsS205 Transient Receptor Potential channelsS219 Voltage‐gated calcium channelsS222 Voltage‐gated proton channelS223 Voltage‐gated sodium channelsS225 AquaporinsS227 Chloride channelsS228 ClC familyS230 CFTRS231 Calcium activated chloride channelS232 Maxi chloride channelS233 Volume regulated chloride channelsS234 Connexins and PannexinsS236 Piezo channelsS237 Sodium leak channel, non‐selectiveS238 Orai channelsS245 Nuclear hormone receptorsS247 1A. Thyroid hormone receptorsS248 1B. Retinoic acid receptorsS249 1C. Peroxisome proliferator‐activated receptorsS250 1D. Rev‐Erb receptorsS251 1F. Retinoic acid‐related orphansS252 1H. Liver X receptor‐like receptorsS253 1I. Vitamin D receptor‐like receptorsS254 2A. Hepatocyte nuclear factor‐4 receptorsS255 2B. Retinoid X receptorsS255 2C. Testicular receptorsS256 2E. Tailless‐like receptorsS256 2F. COUP‐TF‐like receptorsS257 3B. Estrogen‐related receptorsS257 4A. Nerve growth factor IB‐like receptorsS258 5A. Fushi tarazu F1‐like receptorsS259 6A. Germ cell nuclear factor receptorsS259 0B. DAX‐like receptorsS260 Steroid hormone receptorsS260 3A. Estrogen receptorsS261 3C. 3‐Ketosteroid receptorsS264 Catalytic receptorsS266 Cytokine receptor familyS266 IL‐2 receptor familyS268 IL‐3 receptor familyS268 IL‐6 receptor familyS270 IL‐12 receptor familyS271 Prolactin receptor familyS272 Interferon receptor familyS273 IL‐10 receptor familyS274 Immunoglobulin‐like family of IL‐1 receptorsS275 IL‐17 receptor familyS276 GDNF receptor familyS277 IntegrinsS281 Pattern recognition receptorsS281 Toll‐like receptor familyS283 NOD‐like receptor familyS285 RIG‐I‐like receptor familyS285 Receptor guanylyl cyclase (RGC) familyS286 Transmembrane guanylyl cyclasesS287 Nitric oxide (NO)‐sensitive (soluble) guanylyl cyclaseS288 Receptor tyrosine kinases (RTKs)S289 Type I RTKs: ErbB (epidermal growth factor) receptor familyS290 Type II RTKs: Insulin receptor familyS291 Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor familyS292 Type IV RTKs: VEGF (vascular endothelial growth factor) receptor familyS293 Type V RTKs: FGF (fibroblast growth factor) receptor familyS294 Type VI RTKs: PTK7/CCK4S294 Type VII RTKs: Neurotrophin receptor/Trk familyS295 Type VIII RTKs: ROR familyS296 Type IX RTKs: MuSKS296 Type X RTKs: HGF (hepatocyte growth factor) receptor familyS297 Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor familyS297 Type XII RTKs: TIE family of angiopoietin receptorsS298 Type XIII RTKs: Ephrin receptor familyS299 Type XIV RTKs: RETS299 Type XV RTKs: RYKS300 Type XVI RTKs: DDR (collagen receptor) familyS300 Type XVII RTKs: ROS receptorsS301 Type XVIII RTKs: LMR familyS301 Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor familyS302 Type XX RTKs: STYK1S302 Receptor serine/threonine kinase (RSTK) familyS303 Type I receptor serine/threonine kinasesS304 Type II receptor serine/threonine kinasesS304 Type III receptor serine/threonine kinasesS305 RSTK functional heteromersS306 Receptor tyrosine phosphatase (RTP) familyS308 Tumour necrosis factor (TNF) receptor familyS313 EnzymesS318 Acetylcholine turnoverS318 Adenosine turnoverS321 Amino acid hydroxylasesS322 L‐Arginine turnoverS336 2.1.1.‐ Protein arginine N‐methyltransferasesS322 ArginaseS323 Arginine:glycine amidinotransferaseS323 Dimethylarginine dimethylaminohydrolasesS324 Nitric oxide synthasesS325 Carbonic anhydrasesS325 Carboxylases and decarboxylasesS326 CarboxylasesS327 DecarboxylasesS328 Catecholamine turnoverS330 Ceramide turnoverS331 Serine palmitoyltransferaseS331 Ceramide synthaseS332 Sphingolipid Δ4‐desaturaseS332 Sphingomyelin synthaseS333 Sphingomyelin phosphodiesteraseS333 Neutral sphingomyelinase coupling factorsS334 Ceramide glucosyltransferaseS334 Acid ceramidaseS334 Neutral ceramidasesS335 Alkaline ceramidasesS335 Ceramide kinaseS336 Chromatin modifying enzymesS336 2.1.1.‐ Protein arginine N‐methyltransferasesS337 3.5.1.‐ Histone deacetylases (HDACs)S338 Cyclic nucleotide turnover/signallingS338 Adenylyl cyclases (ACs)S340 Exchange protein activated by cyclic AMP (EPACs)S341 Phosphodiesterases, 3’,5’‐cyclic nucleotide (PDEs)S344 Cytochrome P450S344 CYP1 familyS345 CYP2 family: drug metabolising subsetS346 CYP2 family: physiological enzymes subsetS346 CYP3 familyS347 CYP4 familyS348 CYP5, CYP7 and CYP8 familiesS349 CYP11, CYP17, CYP19, CYP20 and CYP21 familiesS350 CYP24, CYP26 and CYP27 familiesS350 CYP39, CYP46 and CYP51 familiesS351 DNA topoisomerasesS351 E3 ubiquitin ligase componentsS352 Endocannabinoid turnoverS353 N‐Acylethanolamine turnoverS354 2‐Acylglycerol ester turnoverS355 Eicosanoid turnoverS355 CyclooxygenaseS356 Prostaglandin synthasesS358 LipoxygenasesS359 Leukotriene and lipoxin metabolismS359 GABA turnoverS361 Glycerophospholipid turnoverS361 Phosphoinositide‐specific phospholipase CS363 Phospholipase A2S364 Phosphatidylcholine‐specific phospholipase DS365 Lipid phosphate phosphatasesS366 Phosphatidylinositol kinasesS368 Phosphatidylinositol phosphate kinasesS369 Haem oxygenaseS370 Hydrogen sulphide synthesisS371 HydrolasesS373 Inositol phosphate turnoverS373 Inositol 1,4,5‐trisphosphate 3‐kinasesS373 Inositol polyphosphate phosphatasesS374 Inositol monophosphataseS374 Kinases (EC 2.7.x.x)S375 Rho kinaseS375 Protein kinase C (PKC) familyS376 Alpha subfamilyS376 Delta subfamilyS377 Eta subfamilyS377 Iota subfamilyS378 FRAP subfamilyS378 Cyclin‐dependent kinase (CDK) familyS379 CDK4 subfamilyS379 GSK subfamilyS380 Polo‐like kinase (PLK) familyS381 STE7 familyS382 Abl familyS382 Ack familyS383 Janus kinase (JakA) familyS383 Src familyS384 Tec familyS385 RAF familyS385 Lanosterol biosynthesis pathwayS388 Nucleoside synthesis and metabolismS389 Paraoxonase (PON) familyS390 Peptidases and proteinasesS390 Blood coagulation componentsS391 A1: PepsinS391 A22: PresenilinS392 C14: CaspaseS392 M1: Aminopeptidase NS393 M2: Angiotensin‐converting enzymes (ACE and ACE2)S393 M10: Matrix metallopeptidaseS394 M12: Astacin/AdamalysinS394 M28: Aminopeptidase YS395 M19: Membrane dipeptidaseS395 S1: ChymotrypsinS396 T1: ProteasomeS397 S8: SubtilisinS397 S9: Prolyl oligopeptidaseS397 Peptidyl‐prolyl cis/trans isomerasesS399 Poly ADP‐ribose polymerasesS399 Prolyl hydroxylasesS400 Sphingosine 1‐phosphate turnoverS400 Sphingosine kinaseS402 Sphingosine 1‐phosphate phosphataseS402 Sphingosine 1‐phosphate lyaseS403 Thyroid hormone turnoverS404 1.14.13.9 Kynurenine 3‐monooxygenaseS405 2.5.1.58 Protein farnesyltransferaseS405 3.5.3.15 Peptidyl arginine deiminases (PADI)S406 3.6.5.2 Small monomeric GTPasesS406 RAS subfamilyS406 RAB subfamilyS412 TransportersS414 ATP‐binding cassette transporter familyS415 ABCA subfamilyS416 ABCB subfamilyS417 ABCC subfamilyS418 ABCD subfamily of peroxisomal ABC transportersS419 ABCG subfamilyS419 F‐type and V‐type ATPasesS420 F‐type ATPaseS420 V‐type ATPaseS420 P‐type ATPasesS421 P1B P‐type ATPases: Cu+‐ATPasesS421 P2A P‐type ATPases: Ca2+‐ATPasesS422 P2B P‐type ATPases: Ca2+‐ATPasesS422 Na+/K+‐ATPasesS422 H+/K+‐ATPasesS423 P4 P‐type ATPases: Phospholipid‐transporting ATPasesS423 P5 P‐type ATPases: Mn2+‐ATPasesS424 SLC superfamily of solute carriersS425 SLC1 family of amino acid transportersS425 Glutamate transporter subfamilyS427 Alanine/serine/cysteine transporter subfamilyS427 SLC2 family of hexose and sugar alcohol transportersS428 Class I transportersS428 Class II transportersS429 Proton‐coupled inositol transporterS430 SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)S430 SLC3 familyS430 SLC7 familyS432 SLC4 family of bicarbonate transportersS432 Anion exchangersS433 Sodium‐dependent HCO3
− transportersS433 SLC5 family of sodium‐dependent glucose transportersS434 Hexose transporter familyS435 Choline transporterS436 Sodium iodide symporter, sodium‐dependent multivitamin transporter and sodium‐coupled monocarboxylate transportersS437 Sodium myo‐inositol cotransporter transportersS438 SLC6 neurotransmitter transporter familyS439 Monoamine transporter subfamilyS439 GABA transporter subfamilyS440 Glycine transporter subfamilyS442 Neutral amino acid transporter subfamilyS443 SLC8 family of sodium/calcium exchangersS444 SLC9 family of sodium/hydrogen exchangersS444 SLC10 family of sodium‐bile acid co‐transportersS445 SLC11 family of proton‐coupled metal ion transportersS446 SLC12 family of cation‐coupled chloride transportersS448 SLC13 family of sodium‐dependent sulphate/carboxylate transportersS449 SLC14 family of facilitative urea transportersS450 SLC15 family of peptide transportersS453 SLC16 family of monocarboxylate transportersS454 SLC17 phosphate and organic anion transporter familyS454 Type I sodium‐phosphate co‐transportersS455 Sialic acid transporterS455 Vesicular glutamate transporters (VGLUTs)S456 Vesicular nucleotide transporterS456 SLC18 family of vesicular amine transportersS457 SLC19 family of vitamin transportersS458 SLC20 family of sodium‐dependent phosphate transportersS459 SLC22 family of organic cation and anion transportersS460 Organic cation transporters (OCT)S461 Organic zwitterions/cation transporters (OCTN)S461 Organic anion transporters (OATs)S462 Urate transporterS463 Atypical SLC22B subfamilyS464 SLC23 family of ascorbic acid transportersS465 SLC24 family of sodium/potassium/calcium exchangersS466 SLC25 family of mitochondrial transportersS466 Mitochondrial di‐ and tri‐carboxylic acid transporter subfamilyS467 Mitochondrial amino acid transporter subfamilyS468 Mitochondrial phosphate transportersS468 Mitochondrial nucleotide transporter subfamilyS469 Mitochondrial uncoupling proteinsS469 Miscellaneous SLC25 mitochondrial transportersS470 SLC26 family of anion exchangersS470 Selective sulphate transportersS471 Chloride/bicarbonate exchangersS471 Anion channelsS472 Other SLC26 anion exchangersS472 SLC27 family of fatty acid transportersS473 SLC28 and SLC29 families of nucleoside transportersS474 SLC28 familyS475 SLC29 familyS476 SLC30 zinc transporter familyS477 SLC31 family of copper transportersS478 SLC32 vesicular inhibitory amino acid transporterS479 SLC33 acetylCoA transporterS480 SLC34 family of sodium phosphate co‐transportersS481 SLC35 family of nucleotide sugar transportersS482 SLC36 family of proton‐coupled amino acid transportersS483 SLC37 family of phosphosugar/phosphate exchangersS484 SLC38 family of sodium‐dependent neutral amino acid transportersS484 System A‐like transportersS485 System N‐like transportersS485 Orphan SLC38 transportersS486 SLC39 family of metal ion transportersS487 SLC40 iron transporterS488 SLC41 family of divalent cation transportersS489 SLC42 family of Rhesus glycoprotein ammonium transportersS490 SLC43 family of large neutral amino acid transportersS491 SLC44 choline transporter‐like familyS492 SLC45 family of putative sugar transportersS493 SLC46 family of folate transportersS494 SLC47 family of multidrug and toxin extrusion transportersS495 SLC48 heme transporterS495 SLC49 family of FLVCR‐related heme transportersS496 SLC50 sugar transporterS497 SLC51 family of steroid‐derived molecule transportersS498 SLC52 family of riboflavin transportersS499 SLC53 Phosphate carriersS499 SLC54 Mitochondrial pyruvate carriersS500 SLC55 Mitochondrial cation/proton exchangersS500 SLC56 SideroflexinsS501 SLC57 NiPA‐like magnesium transporter familyS501 SLC58 MagT‐like magnesium transporter familyS502 SLC59 Sodium‐dependent lysophosphatidylcholine symporter familyS502 SLC60 Glucose transportersS503 SLC61 Molybdate transporter familyS503 SLC62 Pyrophosphate transportersS504 SLC63 Sphingosine phosphate transportersS504 SLC64 Golgi Ca2+/H+ exchangersS505 SLC65 NPC‐type cholesterol transportersS505 SLC66 Lysosomal amino acid transportersS506 SLCO family of organic anion transporting polypeptides
Introduction
In order to allow clarity and consistency in pharmacology, there is a need for a comprehensive organisation and presentation of the targets of drugs. This is the philosophy of the IUPHAR/BPS Guide to PHARMACOLOGY presented on the online free access database (http://www.guidetopharmacology.org/). This database is supported by the British Pharmacological Society (BPS), the International Union of Basic and Clinical Pharmacology (IUPHAR), the University of Edinburgh and previously the Wellcome Trust. Data included in the Guide to PHARMACOLOGY are derived in large part from interactions with the subcommittees of the Nomenclature amd Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR). A major influence on the development of the database was Tony Harmar (1951‐2014), who worked with a passion to establish the curators as a team of highly informed and informative individuals, with a focus on high‐quality data input, ensuring a suitably validated dataset. The Editors of the Concise Guide have compiled the individual records, in concert with the team of Curators, drawing on the expert knowledge of these latter subcommittees. The tables allow an indication of the status of the nomenclature for the group of targets listed, usually previously published in Pharmacological Reviews. In the absence of an established subcommittee, advice from several prominent, independent experts has generally been obtained to produce an authoritative consensus on nomenclature, which attempts to fit in within the general guidelines from NC‐IUPHAR. This current edition, the Concise Guide to PHARMACOLOGY 2021/22, is the latest snapshot of the database in print form, following on from the Concise Guide to PHARMACOLOGY 2019/20. It contains data drawn from the online database as a rapid overview of the major pharmacological targets. Thus, there are many fewer targets presented in the Concise Guide compared to the online database. The priority for inclusion in the Concise Guide is the presence of quantitative pharmacological data for human proteins. This means that often orphan family members are not presented in the Concise Guide, although structural information is available on the online database. The organisation of the data is tabular(where appropriate) with a standardised format, where possible on a single page, intended to aid understanding of, and comparison within, a particular target group. The Concise Guide is intended as an initial resource, with links to additional reviews and resources for greater depth and information. Pharmacological and structural data focus primarily on human gene products, wherever possible, with links to HGNC gene nomenclature and UniProt IDs. In a few cases, where data from human proteins are limited, data from other species are indicated. Pharmacological tools listed are prioritised on the basis of selectivity and availability. That is, agents(agonists, antagonists, inhibitors, activators, etc.) are included where they are both available (by donation or from commercial sources, now or in the near future) AND the most selective. The Concise Guide is divided into seven sections, which comprise pharmacological targets of similar structure/function. These are G protein‐coupled receptors, ion channels (combining previous records of ligand‐gated, voltage‐gated and other ion channels), catalytic receptors, nuclear hormone receptors, enzymes, transporters and other protein targets. We hope that the Concise Guide will provide for researchers, teachers and students a state‐of‐the art source of accurate, curated information on the background to their work that they will use in the Introductions to their Research Papers or Reviews, or in supporting their teaching and studies. We recommend that any citations to information in the Concise Guide are presented in the following format:Alexander SPH et al. (2021). The Concise Guide to PHARMACOLOGY 2021/22: Overview. Br J Pharmacol 178: S1–S26.In this overview are listed protein targets of pharmacological interest, which are not G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, transporters or enzymes. For obvious reasons, we have included potential drug targets of the SARS‐CoV‐2 virus, despite the current limited pharmacological data.
Acknowledgements
We are extremely grateful to the British Pharmacological Society and the International Union of Basic and Clinical Pharmacology, for financial support of the website and for advice from the NC‐IUPHAR subcommittees. We thank the University of Edinburgh, who host the www.guidetopharmacology.org website. Previously, IUPHAR and the Wellcome Trust (099156/Z/12/Z]) also supported the initiation and expansion of the database. We are also tremendously grateful to the long list of collaborators from NC‐IUPHAR subcommittees and beyond, who have assisted in the construction of the Concise Guide to PHARMACOLOGY 2021/22 and the online database www.GuideToPHARMACOLOGY.org.The authors state that there are no conflicts of interest to disclose.
Adiponectin receptors (provisional nomenclature, ENSFM00500000270960) respond to the 30 kDa complement‐related protein hormone adiponectin (also known as
: adipocyte, C1q and collagen domain‐containing protein; ACRP30, adipose most abundant gene transcript 1; apM‐1; gelatin‐binding protein: Q15848) originally cloned from adipocytes [69]. Although sequence data suggest 7TM domains, immunological evidence indicates that, contrary to typical 7TM topology, the carboxyl terminus is extracellular, while the amino terminus is intracellular [136]. Signalling through these receptors appears to avoid G proteins; modelling based on the crystal structures of the adiponectin receptors suggested ceramidase acivity, which would make these the first in a new family of catalytic receptors [121].
Further reading on Adiponectin receptors
Fisman EZ et al. (2014) Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? Cardiovasc Diabetol
13: 103 [PMID:24957699]Okada‐Iwabu M et al. (2018) Structure and function analysis of adiponectin receptors toward development of novel antidiabetic agents promoting healthy longevity. Endocr J
65: 971‐977 [PMID:30282888]Ruan H et al. (2016) Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol
8: 101‐9 [PMID:26993044]Wang Y et al. (2017) Cardiovascular Adiponectin Resistance: The Critical Role of Adiponectin Receptor Modification. Trends Endocrinol Metab
28: 519‐530 [PMID:28473178]Zhao L et al. (2014) Adiponectin and insulin cross talk: the microvascular connection. Trends Cardiovasc Med
24: 319‐24 [PMID:25220977]
Comments
T‐Cadherin (
, P55290) has also been suggested to be a receptor for (hexameric) adiponectin [47].
Aryl hydrocarbon receptor
The aryl hydrocarbon receptor, highly expressed in the liver and barrier organs, is resident in the cytoplasm bound to the chaperone heat shock protein hsp90. Upon agonist activation, the ligand:aryl hydrocarbon receptor complex migrates to the nucleus and binds the aryl hydrocarbon receptor nuclear translocator (ARNT, P27540, also known as HIF1β). The complex regulates transcription of selected genes through interaction with xenobiotic response elements (XRE). Among the genes regulated by the AHR/ARNT complex are cytochrome P450s, particularly CYP1A1, and the period circadian protein homolog 1 (PER1, O15534). The aryl hydrocarbon receptor is also capable of non‐genomic signalling.
Further reading on Aryl hydrocarbon receptor
Bock KW. (2019) Aryl hydrocarbon receptor (AHR): From selected human target genes and crosstalk with transcription factors to multiple AHR functions. Biochem Pharmacol
168: 65‐70 [PMID:31228464]Bock KW. (2020) Aryl hydrocarbon receptor (AHR) functions: Balancing opposing processes including inflammatory reactions. Biochem Pharmacol
178: 114093 [PMID:32535108]Esser C et al. (2015) The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol Rev
67: 259‐79 [PMID:25657351]Roman ÁC et al. (2018) The aryl hydrocarbon receptor in the crossroad of signalling networks with therapeutic value. Pharmacol Ther
185: 50‐63 [PMID:29258844]Rothhammer V et al. (2019) The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol
19: 184‐197 [PMID:30718831]Shi Y et al. (2020) The aryl hydrocarbon receptor: An environmental effector in the pathogenesis of fibrosis. Pharmacol Res
160: 105180 [PMID:32877693]
Non‐enzymatic BRD containing proteins
Bromodomains bind proteins with acetylated lysine residues, such as histones, to regulate gene transcription. Listed herein are examples of bromodomain‐containing proteins for which sufficient pharmacology exists.
Further reading on Non‐enzymatic BRD containing proteins
Fujisawa T et al. (2017) Functions of bromodomain‐containing proteins and their roles in homeostasis and cancer. Nat Rev Mol Cell Biol
18: 246‐262 [PMID:28053347]Myrianthopoulos V et al. (2019) From bench to bedside, via desktop. Recent advances in the application of cutting‐edge in silico tools in the research of drugs targeting bromodomain modules. Biochem Pharmacol
159: 40‐51 [PMID:30414936]Nicholas DA et al. (2017) BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer. Cell Mol Life Sci
74: 231‐243 [PMID:27491296]Ramadoss M et al. (2018) Targeting the cancer epigenome: synergistic therapy with bromodomain inhibitors. Drug Discov Today
23: 76‐89 [PMID:28943305]Spriano F et al. (2020) Targeting BET bromodomain proteins in cancer: The example of lymphomas. Pharmacol Ther
215: 107631 [PMID:32693114]Tang P et al. (2021) Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development. J Med Chem
64: 2419‐2435 [PMID:33616410]
CD molecules
Cluster of differentiation refers to an attempt to catalogue systematically a series of over 300 cell‐surface proteins associated with immunotyping. Many members of the group have identified functions as enzymes (for example, see CD73 ecto‐5’‐nucleotidase) or receptors (for example, see CD41 integrin, alpha 2b subunit). Many CDs are targeted for therapeutic gain using antibodies for the treatment of proliferative disorders. A full listing of all the Clusters of Differentiation proteins is not possible in the Guide to PHARMACOLOGY; listed herein are selected members of the family targeted for therapeutic gain.
Further reading on CD molecules
Bewersdorf JP et al. (2021) Immune checkpoint inhibition in myeloid malignancies: Moving beyond the PD‐1/PD‐L1 and CTLA‐4 pathways. Blood Rev
45: 100709 [PMID:32487480]Chi Z et al. (2021) Transcriptional and epigenetic regulation of PD‐1 expression. Cell Mol Life Sci
78: 3239‐3246 [PMID:33738533]Gabius HJ et al. (2015) The glycobiology of the CD system: a dictionary for translating marker designations into glycan/lectin structure and function. Trends Biochem Sci
40: 360‐76 [PMID:25981696]Huang MY et al. (2021) Combination therapy with PD‐1/PD‐L1 blockade in non‐small cell lung cancer: strategies and mechanisms. Pharmacol Ther
219: 107694 [PMID:32980443]Vosoughi T et al. (2019) CD markers variations in chronic lymphocytic leukemia: New insights into prognosis. J Cell Physiol
234: 19420‐19439 [PMID:31049958]The endogenous ligands for human PD‐1 are programmed cell death 1 ligand 1 (PD‐L1 aka CD274 (CD274, Q9NZQ7)) and programmed cell death 1 ligand 2 (PD‐L2; PDCD1LG2). These ligands are cell surface peptides, normally involved in immune system regulation. Expression of PD‐1 by cancer cells induces immune tolerance and evasion of immune system attack. Anti‐PD‐1 monoclonal antibodies are used to induce immune checkpoint blockade as a therapeutic intervention in cancer, effectively re‐establishing immune vigilance. Pembrolizumab was the first anti‐PD‐1 antibody to be approved by the US FDA.
Methyllysine reader proteins
Methyllysine reader proteins bind to methylated proteins, such as histones, allowing regulation of gene expression.
Further reading on Methyllysine reader proteins
Daskalaki MG et al. (2018) Histone methylation and acetylation in macrophages as a mechanism for regulation of inflammatory responses. J Cell Physiol
233: 6495‐6507 [PMID:29574768]Furuya K et al. (2019) Epigenetic interplays between DNA demethylation and histone methylation for protecting oncogenesis. J Biochem
165: 297‐299 [PMID:30605533]Levy D. (2019) Lysine methylation signaling of non‐histone proteins in the nucleus. Cell Mol Life Sci
76: 2873‐2883 [PMID:31123776]Li J et al. (2019) Understanding histone H3 lysine 36 methylation and its deregulation in disease. Cell Mol Life Sci
76: 2899‐2916 [PMID:31147750]Shafabakhsh R et al. (2019) Role of histone modification and DNA methylation in signaling pathways involved in diabetic retinopathy. J Cell Physiol
234: 7839‐7846 [PMID:30515789]
Fatty acid‐binding proteins
Fatty acid‐binding proteins are low molecular weight (100‐130 aa) chaperones for long chain fatty acids, fatty acyl CoA esters, eicosanoids, retinols, retinoic acids and related metabolites and are usually regarded as being responsible for allowing the otherwise hydrophobic ligands to be mobile in aqueous media. These binding proteins may perform functions extracellularly (e.g. in plasma) or transport these agents; to the nucleus to interact with nuclear receptors (principally PPARs and retinoic acid receptors [99]) or for interaction with metabolic enzymes. Although sequence homology is limited, crystallographic studies suggest conserved 3D structures across the group of binding proteins.
Further reading on Fatty acid‐binding proteins
Gajda AM et al. (2015) Enterocyte fatty acid‐binding proteins (FABPs): different functions of liver and intestinal FABPs in the intestine. Prostaglandins Leukot Essent Fatty Acids
93: 9‐16 [PMID:25458898]Glatz JF. (2015) Lipids and lipid binding proteins: a perfect match. Prostaglandins Leukot Essent Fatty Acids
93: 45‐9 [PMID:25154384]Hotamisligil GS et al. (2015) Metabolic functions of FABPs–mechanisms and therapeutic implications. Nat Rev Endocrinol
11: 592‐605 [PMID:26260145]Matsumata M et al. (2016) Fatty acid binding proteins and the nervous system: Their impact on mental conditions. Neurosci Res
102: 47‐55 [PMID:25205626]Nguyen HC et al. (2020) Role of the Fatty Acid Binding Proteins in Cardiovascular Diseases: A Systematic Review. J Clin Med
9: [PMID:33105856]Osumi T et al. (2016) Heart lipid droplets and lipid droplet‐binding proteins: Biochemistry, physiology, and pathology. Exp Cell Res
340: 198‐204 [PMID:26524506]Although not tested at all FABPs, BMS309403 exhibits high affinity for FABP4 (pIC50 ˜8.8) compared to FABP3 or FABP5 (pIC50<6.6) [27, 118]. HTS01037 is reported to interfere with FABP4 action [42]. Ibuprofen displays some selectivity for FABP4 (pIC50 5.5) relative to FABP3 (pIC50 3.5) and FABP5 (pIC50 3.8) [68]. Fenofibric acid displays some selectivity for FABP5 (pIC50 5.5) relative to FABP3 (pIC50 4.5) and FABP4 (pIC50 4.6) [68]. Multiple pseudogenes for the FABPs have been identified in the human genome.
Notch receptors
Aberrant Notch signalling is implicated in a number of human cancers [59, 80, 108, 126], and there is intense pharmaceutical activity being directed towards achieving clinically effective Notch pathway inhibition [24, 75].
Further reading on Notch receptors
Fabbro D et al. (2020) Notch Inhibition in Cancer: Challenges and Opportunities. Chimia (Aarau)
74: 779‐783 [PMID:33115560]Moore G et al. (2020) Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives. Cells
9: [PMID:32575680]Palmer WH et al. (2015) Ligand‐Independent Mechanisms of Notch Activity. Trends Cell Biol
25: 697‐707 [PMID:26437585]Previs RA et al. (2015) Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer. Clin Cancer Res
21: 955‐61 [PMID:25388163]Takebe N et al. (2015) Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol
12: 445‐64 [PMID:25850553]
Regulators of G protein Signaling (RGS) proteins
Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein‐coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP‐bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [5, 45, 79, 93, 105, 106, 107, 138, 140].
Further reading on Regulators of G protein Signaling (RGS) proteins
Alqinyah M et al. (2018) Regulating the regulators: Epigenetic, transcriptional, and post‐translational regulation of RGS proteins. Cell Signal
42: 77‐87 [PMID:29042285]Fuentes N et al. (2021) RGS proteins, GRKs, and beta‐arrestins modulate G protein‐mediated signaling pathways in asthma. Pharmacol Ther
223: 107818 [PMID:33600853]Neubig RR et al. (2002) Regulators of G‐protein signalling as new central nervous system drug targets. Nat Rev Drug Discov
1: 187‐97 [PMID:12120503]Sethakorn N et al. (2010) Non‐canonical functions of RGS proteins. Cell Signal
22: 1274‐81 [PMID:20363320]Sjögren B. (2017) The evolution of regulators of G protein signalling proteins as drug targets ‐ 20 years in the making: IUPHAR Review 21. Br J Pharmacol
174: 427‐437 [PMID:28098342]Sjögren B et al. (2010) Thinking outside of the "RGS box": new approaches to therapeutic targeting of regulators of G protein signaling. Mol Pharmacol
78: 550‐7 [PMID:20664002]
RZ family
The RZ family of RGS proteins is less well characterized than the other families. It consists of, RGS17(also known as RGSZ2), RGS19 (also known as GAIP) and RGS20 (with several splice variants including RGSZ1 and Ret‐RGS). All members contain an N‐terminal cysteine string motif [62] which is a site of palmitoylation and could serve functions in membrane targeting, protein stability or aid protein‐protein interactions [2, 62]. However, the function in the case of RZ family RGS proteins is not yet fully understood. Members of the RZ family of RGS proteins are the only RGS proteins that have selective GAP activity for Gαz, a function that resulted in the name of the family [31, 71, 127, 134]. However, the members of the RZ family are able to also GAP Gαi/o members with varying selectivity.
R4 family
The R4 family of RGS proteins is the largest family of RGS proteins with 10 members. Each of the R4 family members contain only small N‐ and C‐termini apart from the RGS domain. The N‐terminal amphipathic helix present in most R4 family members serves an important function in membrane association and can directly bind phospholipids. In contrast to the RGS domain, which is well conserved among members of the R4 family of RGS proteins, the N‐ and C‐termini vary, enabling specificity of non‐GAP functions. Despite the non‐complex structure of these proteins, several R4 family RGS proteins have been shown to possess additional functions apart from acting as GAPs at activated Gα subunits [11, 96].
Further reading on R4 family
Xie Z et al. (2016) R4 Regulator of G Protein Signaling (RGS) Proteins in Inflammation and Immunity. AAPS J
18: 294‐304 [PMID:26597290]
R7 family
The members of the R7 family of RGS proteins [6] are more complex structures than the R4 family and are closely related to the C. elegans homologues EGL‐10 and EAT‐16 that were identified in the early stage of RGS protein research [36, 55]. Apart from the RGS domain, several additional domains are present in these proteins that mediate protein‐protein interactions, sub‐cellular localization and protein stability. All R7 family members form obligatory dimers with Gβ5 through the G‐γ like (GGL) domain and the disheveled‐EGL10‐Pleckstrin homology (DEP) domain [109]. The DEP and DEP helical extension domain interact with R7 binding protein (R7BP) or RGS9 anchoring protein (R9AP; in retina) that serves as a plasma membrane anchoring mechanism [41, 51].
R12 family
The R12 family consisting of RGS10, 12 and 14. RGS12 and 14 are large proteins with additional domains that can participate in protein‐protein interactions and other functions. In contrast, RGS10 is a small protein consisting of the RGS domain and small N‐ and C‐termini, similar to members of the R4 family. However, the sequence homology the RGS10 RGS domain clearly places it in the R12 family [58]. The Gαi/o‐Loco(GoLoco) motif in RGS12 and 14 has GDI activity (for Guanine nucleotide Dissociation Inhibitor) towards Gαi1, Gαi2 and Gαi3 [53, 105]. Through this activity RGS12 and RGS14 can inhibit G protein signaling both by accelerating GTP hydrolysis and by preventing G protein activation. Splice variants of RGS12 and RGS14 also contain membrane targeting and protein‐protein interaction domains [97, 111, 112].
Sigma receptors
Although termed ’receptors’, the evidence for coupling through conventional signalling pathways is lacking. Initially described as a subtype of opioid receptors, there is only a modest pharmacological overlap and no structural convergence with the G protein‐coupled receptors; the crystal structure of the sigma1 receptor [98] suggests a trimeric structure of a single short transmembrane domain traversing the endoplasmic reticulum membrane, with the bulk of the protein facing the cytosol. A wide range of compounds, ranging from psychoactive agents to antihistamines, have been observed to bind to these sites.
Further reading on Sigma receptors
Chu UB et al. (2016) Biochemical Pharmacology of the Sigma‐1 Receptor. Mol Pharmacol
89: 142‐53 [PMID:26560551]Herrando‐Grabulosa M et al. (2021) Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis. Br J Pharmacol
178: 1336‐1352 [PMID:32761823]Sambo DO et al. (2018) The sigma‐1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction. Pharmacol Ther
186: 152‐167 [PMID:29360540]Schmidt HR et al. (2019) The Molecular Function ofσ Receptors: Past, Present, and Future. Trends Pharmacol Sci
40: 636‐654 [PMID:31387763]Su TP et al. (2016) The Sigma‐1 Receptor as a Pluripotent Modulator in Living Systems. Trends Pharmacol Sci
37: 262‐278 [PMID:26869505]Vavers E et al. (2019) Allosteric Modulators of Sigma‐1 Receptor: A Review. Front Pharmacol
10: 223 [PMID:30941035](‐)‐pentazocine also shows activity at opioid receptors. The sigma2 receptor has recently been reported to be TMEM97 [4], a 4TM protein partner of NPC1, the Niemann‐Pick C1 protein, a 13TM cholesterol‐binding protein.
Transthyretin
Transthyretin (TTR) is a homo‐tetrameric protein which transports thyroxine in the plasma and cerebrospinal fluid and retinol (vitamin A) in the plasma. Many disease causing mutations in the protein have been reported, many of which cause complex dissociation and protein mis‐assembly and deposition of toxic aggregates amyloid fibril formation [84]. These amyloidogenic mutants are linked to the development of pathological amyloidoses, including familial amyloid polyneuropathy (FAP) [7, 20], familial amyloid cardiomyopathy(FAC) [49], amyloidotic vitreous opacities, carpal tunnel syndrome [76] and others. In old age, non‐mutated TTR can also form pathological amyloid fibrils [131]. Pharmacological intervention to reduce or prevent TTR dissociation is being pursued as a therapeutic strategy. To date one small molecule kinetic stabilising molecule (tafamidis) has been approved for FAP, and is being evaluated in clinical trials for other TTR amyloidoses.
Further reading on Transthyretin
Adams D et al. (2019) Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol
15: 387‐404 [PMID:31209302]Bezerra F et al. (2020) Modulation of the Mechanisms Driving Transthyretin Amyloidosis. Front Mol Neurosci
13: 592644 [PMID:33362465]Dohrn MF et al. (2020) Targeting transthyretin ‐ Mechanism‐based treatment approaches and future perspectives in hereditary amyloidosis. J Neurochem
[PMID:33155274]Galant NJ et al. (2017) Transthyretin amyloidosis: an under‐recognized neuropathy and cardiomyopathy. Clin Sci
131: 395‐409 [PMID:28213611]Griffin JM et al. (2019) Transthyretin cardiac amyloidosis: A treatable form of heart failure with a preserved ejection fraction. Trends Cardiovasc Med
[PMID:31889610]Excess production and accumulation of TTR causes hereditary transthyretin‐mediated amyloidosis. Two novel drugs are now approved to combat this disease: inotersen(Tegsedi
) [52] and patisiran(Onpattro
) [46]. Both of these drugs act to reduce the amount of TTR protein (both wild type and mutant) produced in the liver, but by slightly different mechanisms. Inotersen is an antisense oligonucleotide inhibitor of TTR synthesis, whereas patisiran is a double‐stranded small interfering RNA (which targets a conserved sequence in the 3’ UTR of mutant and wild‐type TTR mRNA). Inotersen is administered subcutaneously, and patisiran is delivered by intravenous infusion in a lipid nanoparticle formulation.
Tubulins
Tubulins are a family of intracellular proteins most commonly associated with microtubules, part of the cytoskeleton. They are exploited for therapeutic gain in cancer chemotherapy as targets for agents derived from a variety of natural products: taxanes, colchicine and vinca alkaloids. These are thought to act primarily throughβ‐tubulin, thereby interfering with the normal processes of tubulin polymer formation and disassembly.
Further reading on Tubulins
Arnst KE et al. (2019) Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy. Med Res Rev
39: 1398‐1426 [PMID:30746734]Boiarska Z et al. (2021) Microtubule‐targeting agents and neurodegeneration. Drug Discov Today
26: 604‐615 [PMID:33279455]Eshun‐Wilson L et al. (2019) Effects of α‐tubulin acetylation on microtubule structure and stability. Proc Natl Acad Sci USA
116: 10366‐10371 [PMID:31072936]Gadadhar S et al. (2017) The tubulin code at a glance. J Cell Sci
130: 1347‐1353 [PMID:28325758]Magiera MM et al. (2018) Tubulin Posttranslational Modifications and Emerging Links to Human Disease. Cell
173: 1323‐1327 [PMID:29856952]Penna LS et al. (2017) Anti‐mitotic agents: Are they emerging molecules for cancer treatment? Pharmacol Ther
173: 67‐82 [PMID:28174095]
SARS‐CoV‐2
Coronaviruses are large, often spherical, enveloped, single‐stranded positive‐sense RNA viruses, ranging in size from 80–220 nm. Their genomes and protein structures are highly conserved. Three coronaviruses have emerged over the last 20 years as serious human pathogens: SARS‐CoV was identified as the causative agent in an outbreak in 2002–2003, Middle East respiratory syndrome (MERS) CoV emerged in 2012 and the novel coronavirus SARS‐CoV‐2 emerged in 2019–2020. SARS‐CoV‐2 is the virus responsible for the infectious disease termed COVID‐19 (WHO Technical Guidance 2020).Alexander SPH et al. (2020) A rational roadmap for SARS‐CoV‐2/COVID‐19 pharmacotherapeutic research and development: IUPHAR Review 29. Br J Pharmacol, 177 (21): 4942‐4966. [PMID:32358833]Cannalire R et al. (2020) Targeting SARS‐CoV‐2 Proteases and Polymerase for COVID‐19 Treatment: State of the Art and Future Opportunities. J Med Chem, [Epub ahead of print]. [PMID:33186044]Cui J et al. (2019) Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol, 17 (3): 181‐192. [PMID:30531947]Desforges M et al. (2019) Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?. Viruses, 12 (1). [PMID:31861926]Song Z et al. (2019) From SARS to MERS, Thrusting Coronaviruses into the Spotlight. Viruses, 11 (1). [PMID:30646565]Zumla A et al. (2016) Coronaviruses ‐ drug discovery and therapeutic options. Nat Rev Drug Discov, 15(5): 327‐47. [PMID:26868298]
Structural proteins
The virus particle has four structural proteins. The envelope, membrane and spike proteins are on the viral surface, while the polybasic nucleoprotein enables the tight coiling of the viral RNA.
Polyproteins
The viral RNA encodes two overlapping polyproteins which are cleaved autocatalytically by intrinsic proteases (see below).
Comment
The component proteins are non‐structural and are involved in the transcription and replication of viral proteins and RNA.
Various types of activating and inactivating NOTCH1 mutations have been reported to be associated with human diseases, for example: aortic valve disease [29, 73], Adams‐Oliver syndrome 5 [114], T‐cell acute lymphoblastic leukemia (T‐ALL) [130], chronic lymphocytic leukemia (CLL) [89] and head and neck squamous cell carcinoma [1, 115].
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Notch receptor 4 is a potential therapeutic molecular target for triple‐negative breast cancer [60, 77].
The sigma2 receptor has been reported to be TMEM97 [4], a 4TM protein partner of NPC1, the Niemann‐Pick C1 protein, a 13TM cholesterol‐binding protein.
By similarity to other coronavirus E proteins, SARS‐CoV‐2 E is predicted to constitute a single transmembrane (potentially homopentameric) ion channel with selectivity for monovalent cations over monovalent anions [85, 119, 133, 139]
The membrane glycoprotein (M) is usually regarded as the most abundant protein in the coronavirus envelope. By similarity with other coronavirus M proteins it is predicted to be essential for initiating assembly of the viral envelope components [94]
The coronavirus nucleocapsid phosphoprotein (N, or nucleoprotein) is highly basic and binds the viral RNA as a dimeric entity [25] into nucleocapsids which protect the viral genome, while also providing access for replication when required
The spike protein extends from the viral surface and binds to the host cell surface enzyme ACE2 to facilitate viral entry into the cell
Nomenclature
Replicase polyprotein 1a
Replicase polyprotein 1ab
Other names
Polyprotein 1a
Polyprotein 1ab
UniProt
P0DTC1
P0DTD1
Function
The replicase polyprotein 1a (pp1a) encodes a set of 11 smaller proteins, including two proteases that are responsible for cleaving the polyprotein chain into its component parts
The replicase polyprotein 1ab (pp1ab) encodes a set of 16 smaller proteins (5 more than pp1a)
The 3C‐like protease cleaves the two polyproteins encoded by the SARS‐CoV‐2 genome (pp1a and pp1ab) into a range of non‐structural proteins (nsp1‐11 from pp1a; nsp1‐16 from pp1ab). As these component proteins play crucial roles in viral replication, the 3C‐like protease is considered to be a good molecular target for drug development. Small molecule 3C‐like protease inhibitors would be predicted to reduce viral replication [33, 85]
The papain‐like protease is a domain within coronavirus Nsp3. Its proteolytic activity cleaves three sites in the viral replicase polyprotein (recognition consensus sequence LXGG↓XX) to release the three non‐structural proteins Nsp1, Nsp2, and Nsp3 [40]. It has additional non‐proteolytic functions as part of the multicomponent replicase‐transcriptase complex [103]
Nomenclature
Non‐structural protein 8
RNA‐dependent RNA polymerase
Other names
Nsp8
non‐structural protein 12, nsp12
UniProt
P0DTC8
P0DTD1
Function
Coronavirus nsp8 proteins form a hexadecameric complex with nsp7 proteins (8 subunits of each) [48, 122]. This complex may participate in viral replication by acting as a primase for de novo initiation of RNA synthesis
The conservation of RdRP catalytic domain between different RNA viruses endows inhibitors that were designed against other viral pathogens with activity against the SARS coronaviruses. Viral RdRP is the molecular target of nucleotide‐based broad‐spectrum antiviral compounds like remdesivir, tenofovir and ribavirin [33, 129, 141]
Nomenclature
Protein 3a
Protein 7a
Protein 9b
Non‐structural protein 6
Non‐structural protein 7b
Other names
Orf3a
Orf7a
Orf9b, Accessory protein 9b, ORF‐9b
Nsp6
Accessory protein 7b, nsp7b
UniProt
P0DTC3
P0DTC7
P0DTD2
P0DTC6
P0DTD8
Function
Protein 3a is a transmembrane pore‐forming viral protein (viroporin) with potassium ion channel activity
The main function of the SARS‐CoV protein 7a appears to be disruption of the host cell cycle and induction of caspase‐dependent apoptosis [120]. By homology SARS‐CoV‐2 protein 7a is likely to produce the same effect
SARS‐CoV protein 9b is a virion‐associated accessory protein [120] that acts to block the host’s ability to mount an antiviral IFN‐induced innate immune response [87]. By homology, 9b from SARS‐CoV‐2 would be predicted to exhibit a similar function
Coronavirus nsp6 proteins limit autophagosome expansion [21]. This mechanism may favour coronavirus infection by damaging autophagosome‐mediated delivery of viral components to lysosomes for degradation
Protein 7b is a coronavirus accessory protein. Experimental evidence suggests that SARS‐CoV 7b has some attenuating function [87]. By homology, SARS‐CoV‐2 7b is likely to have a similar function
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