Structure of G Protein-Coupled Receptors

The key structural elements of the G protein-coupled receptors are seven sequence segments, each made up of 20-30 amino acids, that form a transmembrane domain, and span the membrane in the form of a-helices. The transmembrane elements are linked by loops of various sizes on the outer and inner side. The highest sequence homology of G protein-coupled receptors is found in the transmembrane elements, whilst the hydrophilic loop regions show stronger divergence between different receptors. 

Examplary for the G-protein-coupled receptors, Fig. 5.6 shows the two dimensional model of bovine rhodopsin. The three-dimensional structure of rhodospsin has been directly visualized high resolution X-ray analysis (Palczewski et al., 2000 see Fig 5.3) 

W t E-MI. On the intracellular side, a short helix runs Parallel to the membrane surface. In the native protein, the C-terminus carries two palmitoylated Cys-residues which function as membrane anchors causing formation of a putative fourth intracellular loop. 

Ligands include the biogenic amines (adrenaline, serotonine, doapmine, histamine), neuropetide Y, adenosine, chemokines and melatonine, among others. 

Family B receptors are characterized by a long extracellular N-terminus containing a series of cysteine residues presumably forming a network of disulfide bridges. Representative members of the family B receptors include calcitonine receptor, glucagon receptor and parat hormone receptors. 

Based on sequence data of a large number of G-protein coupled receptors, a distinct structual homology can be demonstrated. The comparable function of the different receptors is reflected in the appearance of common structural elements. 

Due to the common appearance of 7 transmembrane helices, the family of G-protein coupled receptors is also known as the family of the 7-helix transmembrane receptors. The G-protein coupled receptors are also sometimes called the serpentine receptors, pointing to the serpentine-like configuration of transmembrane hehces. 

The G-protein coupled receptors are often glycoproteins. Glycosylation sites are located in the extracellular region, e.g. in the form of the consensus sequence Asn-X-Ser/Thr for an N-linked glycosylation. 

The extracellular loops contain frequently conserved Cys residues. It is assumed that these stabilize the conformation of the extracellular domain, via disulfide bridges. 

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Figure 3.3 Molecular structure of G-protein-coupled receptors. In (a) the electron density map of bovine rhodopsin is shown as obtained by cryoelectron microscopy of two-dimensional arrays of receptors embedded in lipid membrane. The electron densities show seven peaks reflecting the seven a-helices which are predicted to cross the cell membrane. In (b) is shown a helical-wheel diagram of the receptor orientated according to the electron density map shown in (a). The diagram is seen as the receptor would be viewed from outside the cell membrane. The agonist binding pocket is illustrated by the hatched region between TM3, TM5 and TM6. (From Schertler et al. 1993 and Baldwin 1993, reproduced from Schwartz 1996). Reprinted with permission from Textbook of Receptor Pharmacology. Eds Foreman, JC and Johansen, T. Copyright CRC Press, Boca Raton, Florida...

Schwartz, TW (1996) Molecular structure of G-protein coupled receptors. In Textbook of Receptor Pharmacology (Eds Foreman, JC and Johansen, T), CRC Press, Boca Raton, FL, pp. 66-84. 

The problem of characterizing the three-dimensional structure of G-protein-coupled receptors by x-ray crystallography or nuclear magnetic resonance (NMR) has been particularly difficult to solve. The receptors are complicated membrane proteins that are difficult to produce in sufficiently large quantities. When they have been available, it has been difficult to make them form useful... 

Gouldson, P R., Snell, C. R., and Reynolds, C. A. (1997) A new approach to docking in the beta 2-adrenergic receptor that exploits the domain structure of G protein-coupled receptors. J. Med. Chem. 40, 3871-3886. 

The above examples of peptide scaffold- or nonpeptide template-based peptidomimetic agonists or antagonists illustrate various strategies to elaborate bioactive conformation and/or pharmacophore models of peptide ligands at their receptors. In many cases, receptor subtype selectivity has also been achieved by systematic structural modifications of prototypic leads of peptidomimetics. Thus, although the 3D structures of G-protein-coupled receptors (GPCRs) remain as elusive (except for models constructed from homology-based low-... 

Javitch, J. A. (2004). The ants go marching two by two Oligomeric structure of G-protein-coupled receptors. Mol. Pharmacol. 66, 1077-1082. 

Three-dimensional structure of G protein-coupled receptors from speculations to facts. ... 

A FIGURE 13-10 Schematic diagram of the general structure of G protein-coupled receptors. All receptors of this type have the same orientation in the membrane and contain seven transmembrane a-heiical regions (H1-H7), four extracellular segments (E1-E4), and four cytosolic segments (C1-C4). The carboxyl-terminal segment (C4), the C3 loop, and, in some receptors, also the C2 loop are involved in interactions with a coupled trimeric G protein. 

Muller, G. (2000) Towards 3D structures of G protein-coupled receptors A multidisciplinary approach. Curr. Med. Chem. 7 861 - 888. 

Milligan, G. and Bouvier, M. (2005) Methods to monitor the quaternary structure of G protein-coupled receptors. FEES Journal, 272, 2914-2925. 

Cotecchia S et al (2004) Structural determinants involved in the activation and regulation of G protein-coupled receptors lessons from the ai -adrenergic receptor sub-types. Biol Cell 96 327-333... 

Muscarinic acetylcholine receptors (mAChRs) form a class of cell surface receptors that are activated upon binding of the neurotransmitter, acetylcholine. Structurally and functionally, mAChRs are prototypical members of the superfamily of G protein-coupled receptors. Following acetylcholine binding, the activated mAChRs interact with distinct classes of heterotrimeric G proteins resulting in the activation or inhibition of distinct downstream signaling cascades. 

Bondensgaard K, Ankersen M, Thogersen H, Hansen BS, Wulff BS, Bywater RP. Recognition of privileged structures by G-protein coupled receptors. J Med Chem 2004 47 888-99. 

Chemokines are small chemotactic cytokines that act as important messenger molecules between cells of the immune system. Chemokines produce their effects by activating a family of G-protein-coupled receptors. Chemokine receptors are all seven-transmembrane glycoproteins that are structurally related. They may be characterized into those that bind to specific ligands, or those that bind several chemokine ligands. There are also virally encoded (viral) chemokine receptors that represent shared receptors that have been transduced into the viral genome during evolutionary history (Premack and SchaU 1996). 

Teller, D. C., Okada, T., Behnke, C. A., Palczewski, K., and Stenkamp, R. E., Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs), Biochemistry, 40(26), 7761-7772, 2001. 

The 5-HT receptors represent separate and distinct gene products. They can be classified into at least seven classes, designated 5-HTi-7. The 5-HTi, 5-HT2, and 5-HT5 classes consist of five (5-HTia-b-d-e-f)> three (5-HT2a-b-c)> and two (5-HT5a-b) subtypes, respectively, whereas the 5-HT3, 5-HT4, 5-HT6, and 5-HT7 classes have at present one subtype each (Hoyer et al., 1994 Hoyer Martin, 1996 Baez et al., 1995). Except for the 5-HT3 receptor, all other 5-HT receptors are structurally related to the superfamily of G-protein-coupled 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... 

Functional Mechanisms of G Protein-Coupled Receptors in a Structural Context... 

Visiers, I., Ballesteros, J. A., and Weinstein, H. (2002) Three-dimensional representations of G protein-coupled receptor structures and mechanisms. Methods Enzymol 343, 329-371. 

Ballosteros, J A. and Weinstein, H. (1995) Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations of G protein-coupled receptors. Methods in Neurosciences, 25, 366-428. 

Fanelli, F. and De Benedetti, P.G. (2005) Computational modeling approaches to structure-function analysis of G protein-coupled receptors. Chemical Reviews, 105, 3297-3351. 

Javitch JA, Shi L, Liapkis G. 2002. Use of the substituted cysteine accessibility method to study the structure and function of G protein-coupled receptors. Methods Enzymol 343 137-156. 

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