Receptor: Difference between revisions
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*[[Transferrin receptor]] | *[[Transferrin receptor]] | ||
=Intracellular receptors= | =[[Intracellular receptors]]= | ||
==Signal recognition particle receptor== | ==Signal recognition particle receptor== | ||
*[[Signal recognition particle receptor]] | *[[Signal recognition particle receptor]] | ||
Revision as of 15:10, 18 May 2021
Contents
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 5 subunits (A-E) that form an oligomer. In the center of this pentamer of 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 number of residues from each subunit pointed into the binding pocket, as opposed to the large number 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 (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 main contribution to ion selectivity. The M3 and M4 α-helices create a large loop with one another, thus assembling the intracellular region. 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.
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. Full view of the glutamate receptor shows the overall structure (N-terminal, ligand-binding and transmembrane domains) in ribbon and spacefilling models. N-terminal domain is a part of the extracellular domain. This domain is implicated in receptor assembly, trafficking, and localization.
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 7 transmembrane α-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 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 ). 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. The binding of an opioid induces a conformational change in the μ-opioid 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 and activate K+ channels. Activation mechanism. The κ-opioid receptor is a homodimer. The extracellular side is home to the proteins primary active site. These 2 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 α-helices, 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 β-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 α-helices, not β-sheets (Compare β-sheet to α-helices). 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 α-helices (or β-sheet arranged in special fashion called a β-barrel), in order to have maximum stability inside the membrane. 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 κ-opioid receptor ligand binding pocket displays a unique combination of key characteristics both shared with and distinct from those in the chemokine and aminergic receptor families. 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 [2]. When Naltrindole approaches δ-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 [3]. 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[4]. NTSR1 has been mutated to exist in both active and active-like states. 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. 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[5].
hGPR40 contains 7 transmembrane helices (top view of TM helices). hGPR40 and peptide-binding and opioid GPCRs, they share structural similarities such as a conserved hairpin loop motif on extracellular loop 2 (ECL2). A conserved disulphide bond is formed between TM helix 3 (Cys 79) and the C-terminus of ECL2 (Cys170). A unique feature of hGPR40 is the presence of an additional 13 residues (Pro147-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 TM4. 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 TM helices allowing ligands to directly bind from the extracellular space. However, because ECL2 acts as a roof to this 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 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. The binding site for the partial agonist TAK-875 has been identified, but other binding sites were hypothesized. 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 studies. When the substrat/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 tyrosines, Tyr91 and Tyr240. Tyr240 is especially important for binding. 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-Cys170) that forms between TM4 and the C-terminus of the ECL2 loop. 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 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 [6]. TAK-875 binds to the noncanonical binding site. 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. LPA1 lies in the membrane as shown by the fatty acid bound in the crystallization of LPA1. 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). 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 TM α-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 biological ligand of the LPA1 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. 4 separate interactions with this antagonist of LPA1 help demonstrate the key interactions that stabilize the binding of the LPA to this receptor. In the nonpolar region of the binding pocket, 3 nonpolar residues of LPA1 stabilize the 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. 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 6 LPA receptors, a neighboring His residue is specific to the LPA1 receptor. His40 forms both ionic and polar interactions with the carboxylic acid of ON7. Sphingosine-1-phosphate receptor (S1P1) has altered ligand binding pathway (compared to LPA) includes global changes in the positioning of the extracellular loops and transmembrane helices. Specifically, a slight divergence of TMI, which is positioned 3 Å closer to TMVII compared to S1P1, and a repositioning of ECL3, resulting in a divergence of 8 Å from S1P1 result in ligand access via the extracellular space. This narrowing of the gap between TMI and TMVII blocks membrane ligand access in LPA1, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA1. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results from ECL0 lack of secondary structure in LPA1 further promotes favorable LPA access to the binding pocket from the extracellular space.
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.[7]
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 receptorsLDL 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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