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. 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 acetylcholine channel open which releases ions used in creating an action potential. 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. The 2nd 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) 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 α-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 Tutorial: The opioid receptor, a molecular switch You can check out the structure in the window on the right. It shows the mu opioid receptor bound to a peptide ligand and a G protein . The G protein ("G" because it binds to GTP) consists of three parts A , B , and C ). Mu Opioid Receptor Bound to a Morphinan Antagonist In this crystal structure of the μ opioid receptor it is bound to β-funaltrexamine (β-FNA), a close relative of morphine that is bound in the pocket. μ Opioid Receptors Mu Opioid Receptor In the case of the μ-opioid receptor, the binding of an opioid signaling molecule induces a conformational change in the receptor that activates an inhibitory G-protein (Gαi/o). This results in the dissociation of the G-protein complex. The Gα subunit then inhibits adenylyl cyclase. The Gβγ subunit acts to inhibit Ca2+ channels while activing K+ channels. While much has been learned about μ-opioid receptors since their discovery in 1973, there is still much that is unknown about their structure and activation mechanism. The κ-opioid receptor binds opium-type ligands The κ-opioid receptor is a dimer composed of two identical subunits. The extracellular side is home to the proteins primary active site. These two units will span the length for the cell membrane to form the basis of the receptor molecule. The each subunit is attached to the other by the I, II and VIII alpha helices. This can be seen here where helices I (in light blue) and helices VIII (in dark blue). This area will make up the basis for the intermembrane surface area. A distinguishing feature that separates the κ-opioid receptor from other receptors, is the large beta hairpin, ECL2, located near the main active site of the protein. It is believed that its function is to cap the active site of the receptor. Although in general, this protein is primarily composed of alpha helices, not beta sheets (Compare beta sheet to alpha helices here). This evidence reinforces the idea that this protein is a transmembrane protein rather than one found inside the cytosol. In general transmembrane protein are composed almost entirely of alpha helices (or beta sheets arranged in special fashion called a beta barrel), in order to have maximum stability inside the membrane. Another interesting feature of the κ-opioid receptor is the disulfide bond formed by Cys131 and Cys210 which is conserved across all opioid receptors. Active site of κ-opioid receptor. The human kappa opioid receptor (hKOR) ligand binding pocket displays a unique combination of key characteristics both shared with and distinct from those in the chemokine and aminergic receptor families. The δ-opioid receptor binds enkephalins Opioid receptors typically have 2 big portions: the upper portion, zoomed in here with active site shown in indigo, that is ligand specific and recognizes a particular ligand, and the lower portion which is highly conserved amongst all receptors . When Naltrindole approaches delta opioid receptor, it is distinguished by the high hydrophobic interaction between the indole group on the ligand and leucine 300 on the receptor. As it glides deeper into the binding site facilitated by the hydrophobic interaction, the hydroxyl group of the tyrosine-like phenol group hydrogen bonds with water molecules which are hydrogen bound to a critical histidine 248. This holds the ligand by having both the phenol group and histidine anchored by a water molecule. The water molecules within the binding pocket flank both the ligand and receptor, serving almost as a scaffolding on which for both components to act. Adjacent to the phenol group, the oxygen of an ether is hydrogen bound to tyrosine 129 of the receptor. On the opposite side of the binding site, Asp128 forms a salt bridge with the charged amino group on the ligand. The rest of the ligand maintains hydrophobic contact with non-polar residues of the binding site. The phenol to water interaction is a conserved interaction between many opioid receptors and their respective ligands as evidenced by many natural antagonists having a tyrosine that interacts with a water molecule in a similar fashion . Neurotensin receptor Like other G protein-coupled receptors, NTSR1 is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing 7 transmembrane alpha helices (PDB code:4GRV) that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a G-protein associated with this receptor. The hydrophobic binding pocket in NTSR1 is located at the top of the protein (Figure 1). NTSR1 also contains an allosteric sodium binding pocket, which is located directly beneath the ligand binding pocket and the two pockets, which are separated by the residue Trp321. NTSR1 has been mutated to exist in both active and active-like states. CXC chemokine receptor type 4 Ligand binding cavity with antagonist citrulline (PDB code 3oe0). Ligand binding cavity with antagonist citrulline, receptor is in spacefill representation. Ligand binding cavity with antagonist citrulline, receptor surface is shown. Orexin and Orexin receptor The Suvorexant (Belsomra) binding pocket is open to the extracellular space through a constricted solvent-accessible channel. A complex network of electrostatic interactions includes salt bridges between the protein and the drug, on both sides of the entry channel. Belsomra and Orexin receptors Hypocretin and receptors Human Follicle-Stimulating Hormone Complexed with its Receptor GPR40 Like most G-protein coupled receptors, hGPR40 contains 7 transmembrane helices (top view of TM helices). To obtain a crystal structure of the protein, 4 stabilizing mutations (L42A, F88A, G103A, Y202F) were made to increase the expression and thermal stability of the protein. These mutations did not significantly impact the enzyme's binding affinity with a known agonist TAK-875. T4 Lysozyme (in crimson) was also added to intracellular loop 3 to aid in the formation of crystals. While there is relatively low sequence identity between hGPR40 and peptide-binding and opioid GPCRs, they do share structural similarities such as a conserved hairpin loop motif on extracellular loop 2 (ECL2). In addition, a conserved disulphide bond is formed between transmembrane helix 3 (Cys 79) and the C-terminus of ECL2 (Cys170). Compared to peptide-binding and opioid GPCRs, which have distinctive β-sheets spanning from transmembrane helix 4 to 5, hGPR40 possesses a shorter B-sheet-like region, which has low B-factors. This reflects the low mobility of the region that limits the overall flexibility of the adjacent portion of ECL2 between Leu171 and Asp175. A unique feature of hGPR40 is the presence of an additional 13 residues (Pro147 to Gly159) on ECL2, which is absent on all the other peptide/opioid receptors. These extra residues form a separate auxiliary loop between the B-sheet-like region and transmembrane 4. Together, the auxiliary loop and ECL2 of hGPR40 function as a roof over the canonical binding site covering it from the central extracellular region. The canonical binding pocket for many other GPCRs is solvent exposed and centrally located between the transmembrane helices allowing ligands to directly bind from the extracellular space. However, because ECL2 acts as a roof to this canonical binding site, it inhibits ligands from entering directly from the extracellular region. Instead, the highly lipophilic nature of hGPRC40’s ligands allow it to enter a noncanonical binding pocket between TM3 and TM4 by moving through the lipid bilayer. FFAs bind to hGPR40 by coordinating its free carboxyl group to 3 amino acids, Arg183, Tyr2240, and Arg258, which are located close to the extracellular domain of hGPR40 on TM5, 6 and 7. Because of the close proximity of these residues to the extracellular domain and the dominantly hydrophobic nature of FFA’s, it is likely that ligand binding occurs close to the plane of the membrane. The binding site for the partial agonist TAK-875 has been identified, but other binding sites were hypothesized. TAK-875 binds between transmembrane helices 3, 4, and 5 and underneath ECL2. hGPR40 has a distinct binding pocket that is established by 8 key residues: Tyr91, Glu172, Arg183, Ser187, Tyr240, Asn241, Asn244, and Arg258 (all individual residues shown in chartreuse). The importance of these residues for agonist binding was determined by alanine site-directed-mutagenesis mutagenesis studies. When the substrate (an agonist) enters the binding pocket, 4 of the 8 key binding residues interact directly with the carboxylate moiety of the agonist by hydrogen bonding to it. These residues include 2 key arginines in the binding pocket, Arg183 and Arg258, and 2 key tyrosine residues, Tyr91 and Tyr240. Tyr240 is especially important for binding, as mutation of Tyr240 caused an eight fold reduction in the binding affinity of TAK-875 and had a significant effect on the binding affinity (KD) of the protein. hGPR40 contains a highly conserved hairpin extracellular loop (ECL2) is the longest and most divergent of the extracellular loops found in proteins (top view of ECL2). The loop is accompanied by a disulfide bond (Cys79 and Cys170) that forms between transmembrane helix 4 and the C-terminus of the ECL2 loop. In hGPR40, ECL2 has two sections: a beta sheet and an auxiliary loop. The β-sheet spans helices 4 and 5 and is shorter in hGPR40 than in other GPCRs. The ECL2 of hGPR40 also differs from that of other proteins because it contains an auxiliary loop of 13 extra residues. The entire extracellular loop has low mobility and flexibility, which allows it to act as a cap for the binding pocket. The only exception to the low flexibility is the tip of the auxiliary loop, which corresponds to residues Asp152-Asn155. This area of greater mobility allows for substrates to enter the binding site. Tak-875 is a partial agonist of GPR40 and tested for the treatment of type 2 diabetes. The binding of TAK-875 to hGPR40 occurs by the ligand entering the binding site through the membrane bilayer. This membrane insertion is performed via a method similar to ligand binding to sphingosine 1-phosphate receptor 1, retinal loading of GPCR opsin, and the entry of anandamide in cannabinoid receptors, in which the extracellular loops block the binding from the extracellular matrix . TAK-875 binds to the noncanonical binding site created between transmembrane (TM) domains 3-5 and the extracellular loop 2 (ECL2) of hGPR40. The ECL2 and auxiliary loop form a roof causing TAK-875 to enter through TM3 and TM4, first passing through the lipid bilayer. The carboxylate of TAK-875 is buried within a very hydrophobic region and in a complex complex charge network involving Glu172, Ser187, Asn241, and Asn 244 from hGPR40 forming ionic and polar interactions by coordinating TAK-875 with Arg183, Arg258, Tyr91, and Tyr240. Lysophosphatidic acid receptor LPA1 lies in the membrane as shown by the fatty acid bound in the crystallization of LPA1 in orange. Most polar amino acids (red) reside on the intracellular and extracellular areas of the receptor, while most residues positioned on the trans membrane helices inside the membrane are hydrophobic (blue). A cytochrome b (b562RIL) protein was inserted into the 3rd intracellular loop to facilitate crystallization. The intracellular region of this membrane protein is coupled to a heterotrimeric G protein. Three native disulfide bonds in the extracellular region of this receptor provide fold stability. The 1st disulfide bond constrains the N terminal helix to extracellular loop (ECL) 2. The 2nd disulfide bond shapes ECL2, and the 3rd binds ECL3 to one of the transmembrane alpha helices. These disulfide bonds provide intramolecular stabilization along the extracellular region of the LPA1 receptor, where the substrate enters into the binding pocket. The N-terminus is a 6 turn α-helix and functions like a cap on the extracellular side of the protein, packing tightly against ECL1 and ECL2. The N-terminus helix also provides polar amino acids that interact with the ligand when bound. The extracellular region of this receptor plays a role in substrate specificity. The biological ligand of the LPA1 receptor receptor is lysophosphatidic acid (LPA), a phospholipid that contains a long, nonpolar tail, a phosphate head, a chiral hydroxyl group, and an ester group. This receptor provides specificity for its ligand by the amphipathic binding pocket; the positive region on the left hand side of the pocket stabilizes the LPA's phosphate group, the nonpolar region at the bottom of the binding pocket stabilizes the hydrophobic tail of LPA, and the polar region at the top of the pocket stabilize binding of the ester and hydroxyl group. The binding pocket for LPA consists of both polar and nonpolar residues. Polar residues are located on the N terminus and within the binding pocket. A hydrophobic pocket also interacts with the long acyl chain of LPA. The shape and polarity of the binding pocket makes it specific for molecules with a polar head and long hydrophobic tail shaped like LPA. ONO-9780307 (ON7) is an antagonist for LPA due to its large nonpolar region, chiral hydroxyl group, ester, and carboxylic acid which all resemble portions of the LPA molecule (Figure 4). Four separate interactions with this antagonist of LPA1 help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. In the nonpolar region of the binding pocket, three non polar residues of LPA1 stabilize the large nonpolar group of ON7. At the polar region, the ligand binding is stabilized by Arg124 and Glu125 forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between Glu293 and Lys39 causes another stabilizing component with the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a neighboring histidine residue is specific to the LPA1 receptor. His40 forms both ionic and polar interactions with the carboxylic acid of ON7. Protonation of this residue greatly affects the binding affinity of LPA, leading to an increase in the pathways associated with cell proliferation and migration. Because cancerous tumors create acidic environments where His40 is protonated, this residue is an important link to tumor growth and cancer cell movement. 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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