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.
5-HT3 receptor
The 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 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 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 from the binding pocket. This binding pocket shrinks around agonists, encapsulating them, and widens around antagonists, repulsing them.
The 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 , accounting for M2’s main contribution to ion selectivity. The M3 and M4 α-helices create a large with one another, thus assembling the .
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 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.
This representation shows each molecule of the .
Full view of the glutamate receptor shows the overall structure (amino-terminal, ligand-binding and transmembrane domains) in both (MF) and models.
Zooming in at the top of the receptor () (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 () (SM) one can view the transmembrane domain. Here is the same domain separated from the rest of the protein. (DM). This domain widens in response to glutamate binding allowing for positive ions to pass through the post-synaptic membrane.
This view () highlights the area where a receptor antagonist, 2K200225, will bind.
Close up view of the ligand binding site () (AH) of the endogenous ligand glutamate.
The homomeric rat GluA2 receptor arranged in a 'Y'-shape with the . This structure is a functional homotetramer of the AMPA-subtype; native ionotropic glutamate receptors are almost exclusively heterotetramers. .
Domains
The subunits themselves are modular [2]and the major domains are found in layers in the tetrameric structure.
- The 'top' layer is composed of the
- This .
- participates directly in agonist/competitive antagonist binding, affects activation gating, and is the portion that forms the 'middle' layer.
- in the structure.
- The [3], 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[4].
- 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, 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 :
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 -
- .
- And the .
- While that is going on, in the ATD there is also inter-pair interactions mediated between . 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, in the LBD.
- And the .
- While that is going on, in the LBD there is also extensive inter-pair interactions mediated between . Note this view highlights the two-fold symmetry between the A-D and B-C pairs at the level of the LBD. .
- The domain swapping can be observed from the side following the backbone of each chain as well: , , , and . And .
- The . 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.
-
-
- Subunit A is equivalent to Subunit C (in the small structure window in this section). In the main window, a .
- Subunit B is equivalent to Subunit D (in the small structure window in this section). In the main window, a .
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:
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
-
- The segments shown again, .
- There is consistent with the channel being in a closed state with the antagonist ZK200775 bound to the LBD.
- It is that occludes the channel. [BE PATIENT as a small surface is generated.]
- Note . 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, . [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[5][6][7]. Here the pore region of Streptomyces lividans potassium channel (1bl8), specifically the . The 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.[8]
Immune receptors
Leukocyte immunoglobulin-like receptors
Cytokine receptors
TNF receptor superfamily
Type I cytokine receptors
Type II cytokine receptors
Interferon receptors
Interleukin receptors
Interleukin-20 receptor:
Chemokine receptors, two of which acting as binding proteins for HIV (CXCR4 and CCR5). They are G protein-coupled receptors
T-cell receptors
TGF-beta receptor
LDL receptor
Transferrin receptor
Intracellular receptors
Signal recognition particle receptor
Receptor for activated C kinase 1
Nuclear receptors
Endoplasmic reticulum/Sarcoplasmic reticulum receptors
Ligand-gated Calcium channels
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