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 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 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 (β-FNA), a close relative of morphine that is bound in the pocket.
The binding of an opioid induces a 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. .
The κ-opioid receptor is a . The extracellular side is home to the proteins primary . These 2 units will span the length for the cell membrane to form the basis of the receptor molecule. , 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, , 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 to ). 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 formed by Cys131 and Cys210 which is conserved across all opioid receptors. 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 shown in indigo, that is ligand specific and recognizes a particular ligand, and the lower portion which is highly conserved amongst all receptors [1]. When 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 [2].
Like other G protein-coupled receptors, NTSR1 is composed of 3 distinct regions. An where neurotensin binds and causes a conformational change of the protein. A region containing (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 in NTSR1 is located at the top of the protein (Figure 1). NTSR1 also contains an allosteric , which is located directly beneath the ligand binding pocket and the two pockets, which are separated by the residue [3]. NTSR1 has been mutated to exist in both and states.
(PDB code 3oe0).
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.
The through a constricted solvent-accessible channel. A [4].
hGPR40 contains (). hGPR40 and peptide-binding and opioid GPCRs, they share structural similarities such as a conserved motif on (ECL2). A conserved 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 between the B-sheet-like region and TM4. Together, the auxiliary loop and ECL2 of hGPR40 function as a 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 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 by moving through the lipid bilayer. FFAs bind to hGPR40 by coordinating its free carboxyl group to 3 amino acids , which are located close to the of hGPR40. The has been identified, but other binding sites were hypothesized. hGPR40 has a distinct binding pocket that is established by : , , , , , , , and (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 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 () is the longest and most divergent of the extracellular loops found in proteins (). The loop is accompanied by a disulfide bond () 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. 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 block the binding from the extracellular matrix [5]. TAK-875 binds to the . The carboxylate of TAK-875 is buried within a very hydrophobic region and in a complex complex 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 bound in the crystallization of LPA1. Most (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 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 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 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 for LPA consists of both polar and nonpolar residues. residues are located on the N terminus and within the binding pocket. A 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, of LPA1 stabilize the nonpolar group of ON7. At the polar region, the ligand binding is stabilized by forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. Interplay between 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. 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 , which is positioned 3 Å closer to TMVII compared to S1P1, and a repositioning of , 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 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.
Rhodopsin consists of seven mostly α-helical transmembrane domains (H1-H7) linked sequentially by extracellular and cytoplasmic loops (E1-E3 and C1-C3 respectively), with the extracellular amino-terminal tail and the cytoplasmic carboxyl-terminal tail. Four of the helices are tilted and three of the helices are approximately perpendicular to the membrane plane. There is notable interaction between the four extracellular domains, but only a few associations are observed with the cytoplasmic domains. Helix 7 is close to being elongated around the Lysine 296 retinal attachment site, and also contains the residues Proline 291 and Proline 303, with Proline 303 being part of a conserved motif. Near the retinal region, there is a within the Extracellular Helix 2 that runs almost parallel to the chromophore held in place and is stabilized by the essential conserved
. This loop also potentially contacts the chromophore through Glutamine 181 and Tyrosine 191. are observed to be located in the extracellular domains of rhodopsin; specifically, the water molecules around the second extracellular loop between Helix 4 and 5 solvate the loop when the loop interacts with the retinal chromophore and possibly contribute to its flexibility should rearrangement occur. There is the presence of a cationic amphipathic Helix 8, known as the fourth cytoplasmic loop, that spans from and is formed from the C-terminal tail anchoring to the membrane by , which are . This helix runs approximately parallel to the cytoplasmic surface and is involved in Gtγ binding, as well as the modulation of rhodopsin-transducin interactions and rhodopsin-phospholipid interactions. A metal zinc ion bridge chelated by histidine side-chains and connected to the cytoplasmic ends of Helix 3 and 6 is observed to prevent receptor activation. This perhaps indicates that separation of these cytoplasmic ends would contribute to rhodopsin activation. The structure of rhodopsin may provide stability to the important Schiff base linkage with the retinal by affecting its hydrolysis, limiting its interactions with solvent, and inhibiting its release when hydrolyzed, thus encouraging rebinding of the Schiff base linkage.
- 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
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See also Receptor
