Seven-helix receptors

G-Protein coupled receptors (GPCR) represent the start element in secondary messenger producing systems. They comprise a family of over 1000 structurally-related members. These membrane proteins are also called serpentine or seven-helix receptors due to their seven transmembrane domains with an a-helical conformation. Receptors belonging to this class respond to a variety of hormones and neurotransmitters, and they detect odorant molecules or light [3,4]. 

Two pathways from the activated receptor are shown. At the left is activation of phospholipase Cy and formation, at a membrane-bound site, of inositol trisphosphate and diacylglycerol (DAG). The main pathway, in the center, activates Ras with the aid of the G protein Sos. Activated Ras, in turn, activates Raf and successive components of the MAPK cascade. At the right a seven-helix receptor activates both phospholipase C(3 and Ras via interaction with a (3y subunit. (B) A generalized scheme for the MAP kinase pathway. See Seger and Krebs.380... 

Also required by the immune response are the numerous chemokines. Chemoattractant molecules provide concentration gradients that direct the movement of B and T cells and other leukocytes.216 219 Chemokines bind to seven-helix receptors, often... 

Receptors and their ligands are numerous, varied, and essential to all forms of life. Cell-surface receptors on bacteria detect feeding attractants as well as dangerous molecules. From bacteria to humans seven-helix receptors function to detect light, odors, hormones, and other molecules. Tire numbers of different receptors are impressive. For example, the tiny nematode C. elegans has 650 seven-helix transmembrane receptors and 411 protein kinases, many of which may be associated with receptors.34 Our bodies have thousands. 

Xie GX, Miyajima A, Goldstein A. Expression cloning of cDNA encoding a seven-helix receptor from human placenta with affinity for opioid ligands. Proc Natl Acad Sci USA 1992 89 4124-4128. 

A similar situation has occurred with tetrahydrocannabinol (THC). THC acts on a seven-helix receptor that has been identified in those parts of the brain that could... 

Etzkorn M, Martell S, Andronesi OC, Seidel K, Engelhard M, Baldus M. Secondary structure, dynamics, and topology of a seven-helix receptor in native membranes, studied by solid-state NMR spectroscopy. Angew. Chem. Int. Ed. Engl. 2007 46 459-462. 

EF-Ts catalyzes the exchange of GTP for GDP bound to EF-Tu. In G protein cascades, an activated seven-helix receptor catalyzes GTP-GDP exchange in a G protein. For example, photoexcited rhodopsin triggers GTP-GDP exchange in transducin (see Section... 

Donnelly, D. and Findlay, J.B.C. (1994) Seven-helix receptors structure and modelhng, Curr. Opin. Struct. Biol. 4, 582-589. 

G proteins are molecular amplifiers for a large number of seven-trans-membrane helix receptors that regulate responses like vision, smell and stress response. They are heterotrimeric molecules, Gap, that dissociate into membrane-bound Ga and Gpy signal transmitters upon activation of the receptor. 

Seven transmembrane helix receptors Heptahelical receptors Serpentine receptors... 

Alchemical transformations have also been applied to the challenging case of G protein-coupled receptors (GPCRs), for which little structural information is available experimentally at the atomic level. Starting from a template of a seven-helix... 

Figure 8-5 The fluid mosaic model of Singer and Nicolson.61 Some integral membrane proteins, which are shown as irregular solids, are dissolved in the bilayer. Transmembrane proteins protrude from both sides. One of these is pictured as a seven-helix protein, a common type of receptor for hormones and for light absorption by visual pigments. Other proteins adhere to either the outer or the inner surface. Many membrane proteins carry complex oligosaccharide groups which protrude from the outer surface (Chapter 4). A few of these are indicated here as chains of sugar rings.

Integral membrane proteins. Membrane proteins are hard to crystallize178 and precise structures are known for only a few of them.179-181 A large fraction of all of the integral membrane proteins contain one or more membrane-spanning helices with loops of peptide chain between them. Folded domains in the cytoplasm or on the external membrane surface may also be present. The best-known structure of a transmembrane protein is that of the 248-residue bacteriorhodopsin. It consists of seven helical segments that span the plasma membrane (Fig. 23-45) and serves as a light-activated proton pump. Other proteins with similar structures act as hormone receptors in eukaryotic membranes. A seven-helix protein embedded in a membrane is depicted in Fig. 8-5 and also, in more detail, in Fig. 11-6. 

Beta Adrenergic Receptors and Related Seven-Helix Proteins... 

Many other receptors also have a seven-helix structure similar to that of the adrenergic receptors. These include receptors for the following glucagon,... 

Angiotensin II has a variety of effects. By constricting blood vessels it raises blood pressure, and by stimulating thirst centers in the brain it increases blood volume. Both angiotensins II and III also act on the adrenal gland to promote the synthesis and release of aldosterone. Most of the effects of angiotension II are mediated by 359-residue seven-helix G-protein linked receptors which activate phospholipase C.p q qr Like other steroid hormones aldosterone acts,via mineralocorticoid receptors, to control transcription of a certain set of proteins. The end effect is to increase the transport of Na+ across the renal tubules and back into the blood. Thus, aldosterone acts to decrease the loss of Na+ from the body. It promotes retention of water and raises... 

Initially, we attempted to build a 3-D homology model of the transmembrane regions of the human thrombin receptor from the structure of IBRD, which is available from the Brookhaven Protein Database. Unfortunately, the suboptimal placement of several amino acid side chains resulted in severe deviations from structural standards for membrane-bound receptors with a seven-helix bundle topology (Figure 2). For example, carboxylate and ammonium groups on amino acid side chains at a mid-helix location were directed into the membrane, rather than toward the inside of the helix bundle, and the hydrophobic packing between some helices was either poor or nonexistent. 

---