Receptor
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Transmembrane (cell surface) receptorsSee also Membrane proteins. Ion channel-linked (ionotropic) receptorsThese receptors are typically the targets of fast neurotransmitters such as acetylcholine (nicotinic) and GABA; activation of these receptors results in changes in ion movement across a membrane.
5-HT3 receptor The 5-HT3 receptor is bullet-shaped and consists of five subunits (A-E) that form an oligomer. In the center of this pentamer of subunits is a ligand-gated ion channel full of water, which the five subunits enclose pseudo-symmetrically. Each subunit of the 5-HT3 receptor consists of three regions; the extracellular region, the transmembrane region, and the intracellular region[2]. The extracellular region is relatively large compared to the other two regions, and contains a short C-terminus and a larger N-terminus. The N-terminus of the extracellular region is where the ligand binding occurs, and therefore deals with the agonists and antagonists[3]. These binding sites are located between two bordering subunits, assembled from three alpha-helices of one subunit and three beta-strands from the other subunit. Such connection creates a binding pocket with a small, select number of residues from each subunit pointed into the binding pocket, as opposed to the large remainder of residues that are pointing away from the binding pocket[4]. This binding pocket shrinks around agonists, encapsulating them, and widens around antagonists, repulsing them. The transmembrane region is within the C-terminus region, and contains four alpha-helical domains within it (M1-M4) that stretch the length of this inner, transmembrane area. These four alpha-helical domains conduct the channel openings via ion selectivity, depending on both charge and size[4]. M2, the porous domain, contains rings of charged amino acids at both its start and its end, accounting for M2’s main contribution to ion selectivity. The M3 and M4 alpha-helices create a large loop with one another, thus assembling the intracellular region[2]. The extracellular subunit interface of the 5-HT3 receptors: a computational alanine scanning mutagenesis study[5] The serotonin type-3 receptor (5-HT3-R) is a cation selective transmembrane protein channel that belongs to the Cys–loop Ligand-Gated Ion Channel (LGIC) superfamily (https://www.ebi.ac.uk/compneur-srv/LGICdb/LGICdb.php), which also includes receptors for nicotinic acetylcholine (nAChR, PDB code 2bg9), γ-aminobutyric acid and glycine. 5-HT3-R is involved in signal transmission in the central and peripheral nervous system and its malfunctioning leads to neurodegenerative and psychiatric diseases, therefore it is an important target for drug design research. A few drugs active against 5-HT3-R are already on the market, such as, for example, palonosetron (https://en.wikipedia.org/wiki/Palonosetron) and granisetron (https://en.wikipedia.org/wiki/Granisetron). The 5-HT3R is made of five monomers assembled in a pseudo-symmetric pentameric shape to form an ion channel permeable to small ions (Na+, K+); each subunit contains three domains: an intracellular portion, a transmembrane domain and an extracellular region (shown on the example of nAChR, 2bg9). To date, five different 5-HT3-R subunits have been identified, the 5-HT3 A, B, C, D and E; however, only subunits A and B have been extensively characterised experimentally. The ligand binding site of nAChR is located at the extracellular region, at the interface between two monomers (α-γ and α-δ; 2 identical α monomers, chains A and D, are colored in same color - lavender), called the principal and the complementary subunits. The 3D structure of 5-HT3-R has not been experimentally solved yet; however, it has been obtained computationally by means of homology modelling techniques. (https://salilab.org/modeller/) Thus, the extracellular region of the 5HT3 subunits A and B are modelled by homology with the 3D structure of the nAChR subunit A (2bg9-A) and are used to assemble receptor structures as pseudo-symmetric pentamers made either of five identical subunits A (homomeric 5-HT3A-R) or of both subunits A and B (heteromeric 5-HT3A/B-R in the BBABA arrangement) in a still debated arrangement.[6] Subunits A and B are colored in magenta and red, respectively. A complete characterization of the extracellular moiety of the dimer interface of the 5-HT3-R (AA dimer is shown, principal subunit is colored in cyan and complementary is in blue, is obtained by the Computational Alanine Scanning Mutagenesis (CASM) approach [7], which simulates the substitution, one by one, of all the amino acid residues at the subunit-subunit interfaces with an Ala, thus to assess the interface binding contribution of single residue side-chains. The most relevant residues for interface stabilization are classified as “hot spots” that stabilize the interface by more than 4 kcal/mol and “warm spots” that contribute to interface stabilization by more than 2 kcal/mol. Click here to see also the interface of complementary subunit. Interface residues are shown in spacefill representation, hot spot residues are colored in red and warm spots residues are are in orange. From this analysis the important aromatic cluster located at the interface core and formed by residues W178 (principal subunit), Y68, Y83, W85 and Y148 (complementary subunit) is highlighted.[8] In addition, two important groups of interface residues are probably involved in the coupling of agonist and antagonist binding to channel activation/inactivation: W116-H180-L179-W178-E124-F125 (principal subunit) and Y136-Y138-Y148-W85-(P150) (complementary subunit), where W178 and Y148 appear to be critical residues for the binding/activation mechanism. Finally, the comparison of the AA interface with the BB interface (principal subunit of AA is colored in cyan, principal subunit BB is colored in darkmagenta, complementary subunit AA is in blue and complementary subunit BB is in magenta) shows differences which could explain the reasons why the homopentamer 5-HT3B-R, if expressed, is not functional.[9]
G protein-linked (metabotropic) receptorsThis is the largest family of receptors and includes the receptors for several hormones and slow transmitters(dopamine, metabotropic glutamate). They are composed of seven transmembrane alpha helices. The loops connecting the alpha helices form extracellular and intracellular domains. The binding-site for larger peptide ligands is usually located in the extracellular domain whereas the binding site for smaller non-peptide ligands is often located between the seven alpha helices and one extracellular loop. These receptors are coupled to different intracellular effector systems via G proteins
Kinase-linked, enzyme-linked and related receptorsReceptor tyrosine kinasesReceptor tyrosine kinases (RTKs) are part of the larger family of protein tyrosine kinases. They are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Approximately 20 different RTK classes have been identified.[10]
Enzyme-linked receptor
Immune receptorsLeukocyte immunoglobulin-like receptorsCytokine receptorsTNF receptor superfamilyColony-stimulating factor receptorType I cytokine receptorsType II cytokine receptorsInterferon receptors
Interleukin receptorsInterleukin-20 receptor: Chemokine receptors, two of which acting as binding proteins for HIV (CXCR4 and CCR5). They are G protein-coupled receptorsT-cell receptorsTGF-beta receptorLDL receptorTransferrin receptorIntracellular receptorsSignal recognition particle receptorReceptor for activated C kinase 1Nuclear receptors
Endoplasmic reticulum/Sarcoplasmic reticulum receptorsLigand-gated Calcium channelsInositol 1,4,5-Trisphosphate ReceptorRyanodine receptorSEE ALSO:
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