Receptor

spinqualitylabelsall models Nicotinic Acetylcholine Receptor, PDB code 2bg9 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Transmembrane (cell surface) receptors See also Membrane proteins. Ion channel-linked (ionotropic) receptors These 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. Ionotropic receptors 5-hydroxytryptamine receptor#Structural highlights/Specific Function of 5-HT3 The extracellular subunit interface of the 5-HT3 receptors: a computational alanine scanning mutagenesis study 5-hydroxytryptamine receptor#5-HT3 receptor antagonists 5-HT3 receptor The 5-HT3 receptor is bullet-shaped and consists of 5 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 5 subunits enclose pseudo-symmetrically. Each subunit of the 5-HT3 receptor consists of 3 regions; the extracellular region, the transmembrane region, and the intracellular region. The extracellular region is relatively large compared to the other 2 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. These binding sites are located between 2 bordering subunits, assembled from 3 α-helices of 1 subunit and 3 β-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. 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 4 α-helical domains within it (M1-M4) that stretch the length of this inner, transmembrane area. These 4 α-helical domains conduct the channel openings via ion selectivity, depending on both charge and size. 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 α-helices create a large loop with one another, thus assembling the intracellular region. The extracellular subunit interface of the 5-HT3 receptors: a computational alanine scanning mutagenesis study 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 5 monomers assembled in a pseudo-symmetric pentameric shape to form an ion channel permeable to small ions (Na+, K+); each subunit contains 3 domains: an intracellular portion, a transmembrane domain and an extracellular region (shown on the example of nAChR, 2bg9). To date, 5 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 characterized experimentally. The ligand binding site of nAChR is located at the extracellular region, at the interface between 2 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. 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 , 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. In addition, 2 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. Nicotinic Acetylcholine Receptors in general The receptor is a transmembrane pentameric glycoprotein. It cylindrical in appearance by electron microscopy approximately 16nm in length and 8nm in diameter. The main ion channel is composed of a water pore that runs through the entire length of the protein. If viewed from the synaptic cleft, the protein will look like a pseudo-symmetrical rosette shown in the picture below composed of 10 different alpha and 4 different beta subunits. Side view. View from extracellular side. View from cytoplasmic side. Alpha-bungarotoxin is a nicotinic cholinergic antagonist that is found within the venom of Bungarus multicinctus, a South-asian snake. Binding site of AChR Acetylcholine Receptor and its Reaction to Cobra Venom When cobra venom is introduced into the body is moves along the bloodstream to a diaphragm muscle. It works as a postsynaptic neurotoxin binding to the receptor as an extracellular ligand by interacting with OH group leaving the acetyl choline channel open which releases ions used in creating an action potential. Without the ions the diaphragm muscle can not be activated to contract and will not move so an individual can not take a breath. There must be 5 molecules of cobra toxin (red) to block the receptor (blue) as each molecule binds with an individual alpha chain on the acetylcholine receptor. This molecule was generated by overlaying the receptor and venom using Swiss PDB viewer magic fit. The RMS (root mean square difference) of this overlay if 12.21 angstroms involving 185 different atoms. The second image depicts an individual toxin binding with one chain on the receptor, both in the same color. Cobra Venom Interaction with Acetylcholine Receptor This representation shows each molecule of the Cobra toxin binding to one chain of the receptor. AMPA glutamate receptor by University of Massachusetts Amherst Chemistry-Biology Interface Program at UMass Amherst and on display at the Molecular Playground. Full view of the glutamate receptor shows the overall structure (amino-terminal, ligand-binding and transmembrane domains) in both ribbon (MF) and spacefilling models. Zooming in at the top of the receptor (Amino Terminal Domains) (RCB) one can view the amino terminal domain, which is a part of the extracellular domain. This domain is implicated in receptor assembly, trafficking, and localization. Moving toward the bottom of the receptor (Transmembrane Domain) (SM) one can view the transmembrane domain. Here is the same domain separated from the rest of the protein.Transmembrane Domain (DM). This domain widens in response to glutamate binding allowing for positive ions to pass through the post-synaptic membrane. This view (receptor antagonist) highlights the area where a receptor antagonist, 2K200225, will bind. Close up view of the ligand binding site (Glutamate Binding) (AH) of the endogenous ligand glutamate. Glutamate receptor (GluA2) The homomeric rat GluA2 receptor has 4 subunits arranged in a 'Y'-shape with the 'top' being about 3 times the width of the 'bottom'. This structure is a functional homotetramer of the AMPA-subtype; native ionotropic glutamate receptors are almost exclusively heterotetramers. . Domains The subunits themselves are modular and the major domains are found in layers in the tetrameric structure. The 'top' layer is composed of the amino-terminal domain (ATD) This extracellular domain is glycosylated. The ligand-binding domain (LBD) participates directly in agonist/competitive antagonist binding, affects activation gating, and is the portion that forms the 'middle' layer. The competitive antagonist ZK200775 is bound to the LBD in the structure. The ZK200775, a phosphonate quinoxalinedione AMPA antagonist, was studied as a treatment for stroke because it had demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers; however, in a multicenter, double-blind, randomized, placebo-controlled phase II trial, it was found to have significant sedative effects in patients with acute stroke which precludes its further development as a neuroprotective agent. The transmembrane domain (TMD) is the portion that forms the membrane-spanning on the 'bottom' of the solved structure. To help give a better idea of how the glutamate receptor is oriented on the cell surface in the membrane lipid bilayer, a slab representative of hydrophobic core of the lipid bilayer as calculated by the Orientations of Proteins in Membranes database (University of Michigan, USA) is shown with the red patch of spheres indicating the boundary of the hydrophobic core closest to the outside of the cell and the dark blue patch of spheres indicating the boundary closest to the inside of the cell. The carboxy-terminal domain that plays a role in both receptor localization and regulation is not seen in the structure but would be below the transmembrane domain as it is cytoplasmic. Domain swapping between the subunits and symmetry mismatch between the domains Unanticipated is the domain swapping and crossover that occurs between the subunits interactions. In order to discuss the remarkable swapping, it is best to designate each subunit with a letter:     A       B       C        D Considering each chain, there is crossover as the pairs of subunits seen in the ATD are swapped in the LBD. In the ATD domain - Portions of the A and B subunits pair up. And the Portions of the C and D subunits form a pair. While that is going on, in the ATD there is also inter-pair interactions mediated between subunits B and D. Note this view really highlights the two-fold symmetry between the A-B and C-D pairs at the level of the ATD. In the LBD domain - Whereas in the ATD domain A and B paired up, portions of the A and D subunits pair up in the LBD. And the Portions of the B and C subunits form a pair. While that is going on, in the LBD there is also extensive inter-pair interactions mediated between subunits A and C. Note this view highlights the two-fold symmetry between the A-D and B-C pairs at the level of the LBD. Looking from the side helps in seeing the inter-pair interactions between A and C. The domain swapping can be observed from the side following the backbone of each chain as well: A chain, B chain, C chain, and D chain. And all for comparison. The symmetry is an overall four-fold for the TMD. Thus, remarkably, the symmetry switches from an overall two-fold symmetry for the ATD and LBD to four-fold for the TMD. As a result of the swapping and symmetry mismatch, there is subunit non-equivalence; even though all the chains are the same chemically, there are 2 distinct conformations of the subunits. This means there are 2 matching pairs of subunits. A is equivalent to C B is equivalent to D Subunit A is equivalent to Subunit C (in the small structure window in this section). In the main window, a morph showing the equivalency of the 2 subunits by rotating around the axis of their symmetry. Subunit B is equivalent to Subunit D (in the small structure window in this section). In the main window, a morph showing the equivalency of the two subunits by rotating around the axis of their symmetry. However, each of the subunit A/C group though is distinct from those of the B/D group. Having established the two equivalent groups we can simplify the discussion of the relationship between the two pairs by focusing solely on comparing Subunit A' and Subunit B. The domains themselves stay relatively static between the two conformational forms, with the linkers in between and the resulting arrangement changing. This is best illustrated by superposition of the individual domains of Subunit A and Subunit B: Superposition of the ATD. Superposition of the LBD. Superposition of the TMD. Subunit A morphing into Subunit B best illustrates how portions, especially the linkers, of the protein change between the two conformational forms. The linkers are key; besides playing roles in domain swapping and resolving the symmetry mismatch, they are also responsible for relaying the modulation signals from the ATD to the other domains and signaling the conformational change of the LBD to control the opening and closing of the pore. Beyond the two conformations seen here though this particular structure (3kg2) of the receptor does not shed light on the transduction process. Transmembrane domain architecture and the occluded pore Transmembrane segments M1 to M4 depicted in different colors to show the approximate 4-fold rotational symmetry of the entire ion channel domain. M1 M2 M3 M4 The segments shown again, this time parallel to the 4-fold axis. There is no pore visible in the center consistent with the channel being in a closed state with the antagonist ZK200775 bound to the LBD. It is the tight helix crossing of specifically the M3 helices that occludes the channel. [BE PATIENT as a small surface is generated.] Note the differences between the conformations of the carboxy-termini ('top') of the subunit A/C and B/D M3 segments. This is in part is why the symmetry is only approximately four-fold and is one of the several intriguing observations in regard to symmetry for this macromolecule. In fact, the location of 2-fold symmetry at the ends of M3 is just above the portion that spans the membrane and is close to the last region of the structure that doesn't show four-fold symmetry as abruptly below this point everything is 4-fold symmetric. To better observe the contributions of each of the membrane segments to the subunit-subunit interactions, the transmembrane domains of three subunits are shown in a surface representation with the segments M1-M4 of the fourth subunit shown as green cylinders. [Note: this scene generates a substantial surface which may take about a minute to calculate. Be patient.] Note that the M4 segment associates with the ion-channel core of an adjacent subunit. . The TMD domain of the GluA2 receptor shares structural and sequence similarity with the pore region of the potassium (K+), as hinted at by earlier work. Here the pore region of Streptomyces lividans potassium channel (1bl8) superposed with the TMD domain of GluA2, specifically the inner helix of the K+ channel aligned with the M3 segment. The M1 segment of GluA2 also overlays well with the outer helix of the K+ channel even though these portions weren't even included in the calculation of the alignment seen here. G protein-linked (metabotropic) receptors This is the largest family of receptors and includes the receptors for several hormones and slow transmitters (dopamine, metabotropic glutamate). They are composed of 7 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 G protein-coupled receptors Neurotensin receptor CXC chemokine receptor type 4 Mu Opioid Receptor Bound to a Morphinan Antagonist μ Opioid Receptors Mu Opioid Receptor The κ-opioid receptor binds opium-type ligands. The δ-opioid receptor binds enkephalins Tutorial: The opioid receptor, a molecular switch Orexin and Orexin receptor Belsomra and Orexin receptors Hypocretin and receptors Human Follicle-Stimulating Hormone Complexed with its Receptor GPR40 Lysophosphatidic acid receptor Sphingosine 1-phosphate Receptor Rhodopsin Rhodopsin Structure and Function Serotonin receptors, main page 3D structures of Serotonin receptors Adrenergic receptors in general Beta-1 Adrenergic receptor Dobutamine: Beta-1 Adrenergic receptor, 2y00, 2y01, 6h7l Isoprenaline: Beta-1 Adrenergic receptor, 2y03 Carmoterol: 2y02 Salbutamol: 2y04 Adrenergic receptor page. Article Beta-2 Adrenergic Receptor by Wayne Decatur, David Canner, Dotan Shaniv, Joel L. Sussman, Michal Harel Article Beta-2 adrenergic receptor by Joel L. Sussman, Tala Curry, Michal Harel, Jaime Prilusky Group:SMART:A Physical Model of the beta-Adrenergic Receptor Gs: adenylate cyclase activated, cAMP up. For Gs see Beta2 adrenergic receptor-Gs protein complex updated Dopamine receptors 1 page Dopamine receptors 2 page Histamine H1 receptor 3rze - human histamine H1 receptor with an antagonist doxepin Adenosine A2A receptor Effect of Caffeine (Trimethylxanthine) on Human A2A Receptor Muscarinic acetylcholine receptor Glucose-dependent Insulinotropic Polypeptide Receptor Glucagon receptor Glucagon-like peptide 1 receptor Metabotropic Glutamate Receptors Ligand Binding N-Terminal of Metabotropic Glutamate Receptors Metabotropic glutamate receptor 5 Kinase-linked, enzyme-linked and related receptors Receptor tyrosine kinases Receptor 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. RTK class I Epidermal Growth Factor Receptor family RTK class II Insulin receptor family RTK class III Platelet-derived growth factor receptor family RTK class IV Vascular Endothelial Growth Factor Receptor family RTK class V Fibroblast growth factor receptor family RTK class VIII Hepatocyte growth factor receptor family RTK class IX Ephrin receptor family RTK class XIII Epithelial discoidin domain-containing receptor (DDR receptor) family Neurotrophin: High affinity nerve growth factor receptor (or Tyrosine kinase receptor) and TrkB tyrosine kinase receptor Insulin-like growth factor receptor Enzyme-linked receptor TGF-beta receptor Activin receptor Crystal structure of the extracellular domain of the receptor-like kinase TMK3 from Arabidopsis thaliana Bone Morphogenetic Protein 7 and receptor Neurotrophin High affinity nerve growth factor receptor TrkA TrkB tyrosine kinase receptor Toll-like Receptors Immune receptors Leukocyte immunoglobulin-like receptors Leukocyte immunoglobulin-like receptor Cytokine receptors TNF receptor superfamily Tumor necrosis factor receptor TRAIL (TNF-related apoptosis-inducing ligand) or TNF ligand superfamily 10 Type I cytokine receptors Erythropoietin receptor Prolactin receptor Type II cytokine receptors Interferon receptors Interferon receptor Structural linkage between ligand discrimination and receptor activation by type I interferons Multiple sclerosis and Interferon Receptors Interleukin receptors Interleukin receptor Interleukin-20 receptor: Flexible regions govern promiscuous binding of IL-24 to receptors IL-20R1 and IL-22R1 T-cell receptors T-cell receptor SP3.4-TCR-HLA-DQ8-α-1-gliadin complex TGF-beta receptor TGF-beta receptor LDL receptor LDL receptor Transferrin receptor Transferrin receptor Intracellular receptors Signal recognition particle receptor Signal recognition particle receptor Receptor for activated C kinase 1 Receptor for activated protein kinase C 1 Nuclear receptors Nuclear receptors Thyroid hormone receptor Retinoic acid receptor RA Mediated T-reg Differentiation; Retinoic acid acts as the ligand for the Retinoic Acid Receptor-α (RARα) / Retinoid X Receptor-α (RXRα) heterodimer PPAR-gamma Pioglitazone is a selective agonist for Peroxisome Proliferator-Activated Receptor Gamma Liver X receptor Bile acid receptor Vitamin D receptor Pregnane X receptor Retinoid X receptor Estrogen receptor Ivan Koutsopatriy estrogen receptor Estrogen receptor#Structure of estradiol metal chelate and estrogen receptor complex: The basis for designing a new class of SERMs Estrogen receptor#Estrogen receptor α complexed with raloxifene and a corepressor peptide Tamoxifen and the Estrogen receptor Student Project 10 for UMass Chemistry 423 Spring 2015 Estrogen-related receptor Glucocorticoid receptor Mineralocorticoid receptor Progesterone receptor Androgen receptor Liver receptor homolog-1? Endoplasmic reticulum/Sarcoplasmic reticulum receptors Ligand-gated Calcium channels Ryanodine receptor SEE ALSO: Hormones and their receptors Hormone Growth factors Neurotransmitters

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